Redox and photoinitiator systems for priming and improved adherence of gels to substrates

ABSTRACT

An impoved barrier or drug delivery system which is highly adherent to the surface to which it is applied is disclosed, along with methods for making the barrier. In the preferred embodiment, tissue is stained with a photoinitiator, then the polymer solution or gel having added thereto a defined amount of the same or a different photoinitiator is applied to the tissue. On exposure to light, the resulting system polymerizes at the surface, giving excellent adherence, and also forms a gel in the rest of the applied volume. Thus a gel barrier of arbitrary thickness can be applied to a surface while maintaining high adherence at the interface. This process is referred to herein as &#34;priming&#34;. the polymerizable barrier materials are highly useful for sealing tissue surfaces and junctions against leaks of fluids. In another embodiment, &#34;priming&#34; can be used to reliably adhere preformed barriers to tissue or other surfaces, or to adhere tissue surfaces to each other. A first surface and a barrier, or another surface, are prestained with initiator, and a thin layer of gelable monomer containing initiator is placed between them. Strong adhesion is obtained between the two surfaces on gelation of the monomer. In a similar fashion, tissue surfaces can be adhered to each other in repair of wounds and formation of anastomoses. Methods for use of non-photochemical systems and combined chemical/photochemical systems are described.

Priority is claimed under 35 U.S.C. §119 to PCT/US 96/03834, filed Mar.22, 1996, which is a continuation-in-part of U.S. Ser. No. 08/410,037,filed Mar. 23, 1995; U.S. Ser. No. 08/472,745, filed Jun. 7, 1995; andU.S. Ser. No. 08/478,104, filed Jun. 7, 1995.

BACKGROUND OF THE INVENTION

The present invention relates to methods and compositions for improvingthe adherence of polymer gels to surfaces, especially tissue surfaces;devices for applying the compositions and gels; and general methods forsealing surfaces with gels for therapeutic benefit.

Locally polymerized gels have been used as barriers and drug deliverydevices for several medical conditions. Adherence of the formed gel tothe tissue can be a problem, especially under surgical conditions, wherethe tissue surface to be treated is typically wet, and may further becovered with blood, mucus or other secretions. Hubbell and co-workershave described two methods for photopolymerizing gels in contact withtissue surfaces. In U.S. Pat. No. 5,410,016, hereby incorporated byreference, application of biodegradable macromers to tissue, followed byphotopolymerization to form a gel, is described. Two methods forphotopolymerizing gels are described. In "bulk" polymerization, asuitable photoinitiator and accessory reagents are solubilized ordispersed in a solution of gelling macromers. On application of light,the entire solution volume crosslinks to form a gel which acts as alocal barrier or drug depot. These gels have substantial adherence tomost surfaces, including tissue surfaces which are merely moist.However, if a confounding layer of fluid is present on the surface whenthe macromer/initiator solution is applied, then the gel may delaminatefrom the surface after its formation.

An alternative way of form a gel layer on a surface, as also describedin U.S. Ser. No. 08/024,657, which is hereby incorporated by reference,is called the "interfacial" method. In this method, the surface to becoated is treated with a photoinitiator which adsorbs or absorbs to thesurface. After washing away excess, unabsorbed photoinitiator, apolymerizable macromer solution is applied to the surface. On exposureto light, polymerization is initiated at the surface, and progressesoutward into the solution to the limit of diffusion of thephotoinitiator-generated radicals during their lifespan. Coatingthicknesses of up to about 500 micrometers (microns) are routinelyobtained. Since they are in effect "grown" from the tissue surface, suchgel layers have excellent adhesion to the tissue surface under difficultconditions, including the presence of thin layers of fluid adherent tothe surface. The limited thickness of such interfacial gels is desirablein some circumstances, but represents a major limitation where gels ofsubstantially greater thickness than 500 microns are required, forexample, for use in drug delivery, or in forming an effective barrierbetween the tissue surface and its surroundings.

In addition to the photopolymerizable gels described by Hubbell et al(WO 93/17669) and Sawhney et al, (J. Biomed. Mats. Res. 28, 831-838,1994), systems for forming drug delivery depots or barriers on surfacesinclude the polymers described in U.S. Pat. No. 4,938,763 to Dunn, etal., U.S. Pat. Nos. 5,100,992 and 4,826,945 to Cohn et al, U.S. Pat.Nos. 4,741,872 and 5,160,745 to De Luca et al, and U.S. Pat. No.4,511,478 to Nowinski et al. Use of preformed barrier materials such asGoretex™ membrane (W. L.Gore) has been described in the literature.

Although all of these materials are suitable for application to tissueand other substrates, adhesion is in many cases limited, or in the caseof the preformed barrier materials, essentially non-existent.

It is therefore an object of the present invention to provide methodsand compositions for enhancing the adhesion of polymeric materials totissue surfaces and other substrates.

It is a further object of the present invention to provide methods andcompositions for increasing the thicknesses of polymeric materials whichcan be "tethered" to a tissue surface or other substrates.

It is a further object of the present invention to provide improvedinitiator systems for the formation of gels on tissues and othersurfaces.

It is a further object of the present invention to provide improvedmethods and new medical indications for the sealing and coating oftissue.

It is a further object of the present invention to provide devicessuitable for performing these operations.

SUMMARY OF THE INVENTION

An improved barrier, coating or drug delivery system which is highlyadherent to the surface to which it is applied is disclosed, along withmethods for making the barrier. In the preferred embodiment, tissue isstained with a photoinitiator, then the polymer solution or gel incombination with a defined amount of the same or a differentphotoinitator is applied to the tissue. On exposure to light, theresulting system polymerizes at the surface, giving excellent adherence,and also forms a gel throughout the illuminated volume. Thus a gelbarrier or coating of arbitrary thickness can be applied to a surfacewhile maintaining high adherence at the interface. This process isreferred to herein as "priming". The polymerizable barrier materials arehighly useful for sealing tissue surfaces and junctions against leaks offluids. In the examples described below, the fluids are air and blood;however, the principle is also applicable to other fluids, includingbowel contents, urine, bile, cerebrospinal fluid, vitreous and aqueoushumors and other fluids whose migration within a living organism must becontained.

In another embodiment, "priming" can be used to reliably adherepreformed barriers or coatings to tissue or other surfaces, or to adheretissue surfaces to each other. A first surface and a preformed barrieror coating, or another surface, are prestained with initiator, and athin layer of polymerizable monomer containing initiator is placedbetween them. Strong adhesion is obtained between the two surfaces onpolymerization of the monomer. In a similar fashion, tissue surfaces canbe adhered to each other in repair of wounds and formation ofanastomoses.

The priming method is suitable for any mode of polymerization. Whileespecially effective in photopolymerization, chemical or thermalpolymerization can also be accomplished by this method. Further, anenhancement of photoinitiation can be achieved by adding suitable redoxinitiation components to the system, providing a new form oflight-controlled chemically accelerated polymerization reaction,especially effective in the presence of blood.

According to one embodiment, the invention provides a device fordispensing a fluid to a tissue surface in a medical setting, having aproximal portion operable by a user of the device and a distal portionhaving an applicator outlet for addressing the tissue surface. Thedevices is characterized in that it includes at least two chambers forreceiving fluids to be dispensed to the tissue surface and conduitsconnecting each chamber to an applicator outlet at the distal portion ofthe device. The device also includes an optical emitter at the distalportion for applying light to the fluid at the tissue surface.

According to another embodiment, the invention provides a device fordispensing a fluid to a tissue surface as described above, characterizedin that it includes at least two chambers for receiving fluids to bedispensed to the tissue surface and conduits connecting each chamber toan applicator outlet at the distal portion of the device, a firstdispensing mechanism activating dispensing of fluid from the firstchamber to the tissue surface, operably linkable to a trigger at theproximal portion, and a second dispensing mechanism activatingdispensing of fluid from the second chamber to the tissue surface,operably linkable to a trigger at the proximal portion.

According to another embodiment, the invention provides a dispensingadapter for use in a medical setting. The adapter operates by attachmentto a device having a reservoir for containing a fluid to be dispensed toa tissue surface and a fluid outlet, and is characterized in that it isfastenable to the device and removable therefrom, and includes a conduithaving a proximal end connectable in a fluid-tight manner to the fluidoutlet of the device, a distal end defining a adapter fluid outlet, anda spreading member at the distal end adapted to spread fluid dispensedfrom the adapter fluid outlet on the tissue surface.

The invention also provides a dispensing adapter for use in a medicalsetting by attachment to a device having a reservoir for containing afluid to be dispensed to a tissue surface and a fluid outlet. Thedispensing adapter is characterized in that it includes an opaquechamber for containing the device, an opaque conduit having a proximalend connectable in a fluid-tight manner to the fluid outlet of thedevice, and a distal end defining a adapter fluid outlet

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1a and 1b are schematic drawings of a two-fluid-one-dispenserversion of an application device, in which FIG. 1a is a longitudinalschematic cross-section and FIG. 1b is a view from the proximal end ofthe device.

FIG. 2 is a schematic drawing of an alternate embodiment of a deliverydevice.

FIG. 3 is a graph of the relative adherence to tissue of severalformulations, on a scale where a higher score indicates pooreradherence.

FIG. 4 is a schematic drawing of a dispenser according to anotherembodiment.

FIG. 5 is a cross-sectional view of the dispenser illustrated in FIG. 4with the upper assembly detached.

FIG. 6 is a cross-sectional view through section 6--6 of FIG. 4.

FIG. 7 is a front view of the device illustrated in FIG. 4.

FIG. 8 is a partial cross-sectional view through line B--B of FIG. 4.

FIG. 9 illustrates schematically a dispenser arrangement according toanother embodiment of the invention.

FIG. 10 illustrates schematically the arrangement of FIG. 9, asassembled.

FIG. 11 illustrates schematically the use of the device illustrated inFIG. 10 in conjunction with a light wand.

DETAILED DESCRIPTION OF THE INVENTION

As described herein, one or more initiators are applied to a surface toform an absorbed layer. "Absorbed" is used herein to encompass both"absorbed" and "adsorbed". A solution of polymerizable molecules,referred to herein as "monomers", is then applied.

Methods

There are several embodiments of the method described herein.

In its simplest embodiment, one or more initiators or components of aninitiation system are applied directly to the surface, and theunabsorbed excess is optionally removed by washing or blotting. Theinitiator solution may further contain one or more polymerizablemonomers, and other useful formulating ingredients, includingaccelerators, co-initiators, sensitizers, and co-monomers. Then a liquidcontaining polymerizable monomers in combination with one or moreinitiators or components of an initiation system, which may be the sameas or different from that absorbed in the first step, is applied. Thesystem, if not self-polymerizing, is then stimulated to polymerize, forexample by application of an appropriate wavelength of light.

The priming and monomer-application steps can also be combined. Forexample, if excess initiator is not removed before monomer addition,then subsequent application of monomer will result in mixture ofinitiator into the monomer layer. Similarly, if the monomer layercontains an initiator with a high affinity for the surface, then it ispossible to apply a monomer layer containing initiator, and wait anappropriate time to allow preferential absorption of the initiator tothe surface, to achieve the same effect.

All of these methods may collectively be described as application of themonomer in an "initiating-incorporating manner", encompassing any meansof application and mixing which results in both an absorbed layer ofinitiator, and a layer of monomer incorporating an initiator, beingpresent on a surface to be coated.

The initiators may be chemical, photochemical, or a combination thereof.With non-photochemical systems, a reductant component and an oxidantcomponent may be present in the two parts of the solution, i.e., in thepriming layer and the coating layer.

Alternatively, a two-step process can be used to form polymers,especially bioabsorbable hydrogels on tissue. In the first step thetissue is treated with an initiator or a part of an initiator system forthe polymerization of olefinic (e.g. acrylic) or other functionalmonomers, optionally with monomer in the priming solution. This providesan activated tissue surface. In the second step, monomer(s) and, ifappropriate, the remainder of an initiator system, are together placedin contact with the activated tissue, resulting in polymerization on thetissue. An example of such a system is the combination of a peroxygencompound in one part, and a reactive ion, such as a transition metal, inanother.

This process of spontaneous polymerization does not require the use of aseparate energy source. Moreover, since the process of polymerization isinitiated when part one contacts part two, there are no "pot life"issues due to initiation of polymerization. If desired, part one or parttwo can contain dyes or other means for visualizing the hydrogelcoating.

An example of a system that can be used in this method is thespontaneous "contact" initiator systems such as those found in two part"acrylic structural adhesives". All components of the materials used asdescribed herein, however, must display biocompatibility as well as theability to spontaneously polymerize on tissue. The use of tributylborane for this purpose is illustrated here. These systems can markedlysimplify the delivery of gel to tissue, especially in areas hard toreach or hold for a photochemical system. The delivery system can bemuch simpler. Moreover, it has been discovered that a two-part chemicalsystem such as a redox system and especially one based on peroxygen, canbe used to chemically enhance the curing of a photochemical system,thereby combining the control of a photochemical system with the abilityof a chemical system to overcome colored impurities, such as blood.

Compositions

MONOMERS

Any monomer capable of being polymerized to form a surface coating canbe used. The monomers may be small molecules, such as acrylic acid orvinyl acetate; or they may be larger molecules containing polymerizablegroups, such as acrylate-capped polyethylene glycol (PEG-diacrylate), orother polymers containing ethylenically-unsaturated groups, such asthose of U.S. Pat. No. 4,938,763 to Dunn et al, U.S. Pat. Nos. 5,100,992and 4,826,945 to Cohn et al, U.S. Pat. Nos. 4,741,872 and 5,160,745 toDe Luca et al., or U.S. Pat. No. 5,410,016 by Hubbell et al. Propertiesof the monomer, other than polymerizability, will be selected accordingto the use, using principles as known in the art. There is an extensiveliterature on the formulation of polymerizable coating materials forparticular applications; these formulae can readily be adapted to usethe improved adherence-promoting polymerization system described hereinwith little experimentation.

In the particular application area of coating of tissues, cells, medicaldevices, and capsules, formation of implants for drug delivery or asmechanical barriers or supports, and other biologically related uses,the general requirement of the coating materials are biocompatibilityand lack of toxicity. For all biologically-related uses, toxicity mustbe low or absent in the finished state for externally coated non-livingmaterials, and at all stages for internally-applied materials.Biocompatibility, in the context of biologically-related uses, is theabsence of stimulation of a severe, long-lived or escalating biologicalresponse to an implant or coating, and is distinguished from a mild,transient inflammation which accompanies implantation of essentially allforeign objects into a living organism.

The monomer solutions should not contain harmful or toxic solvents.Preferably, the monomers are substantially soluble in water to allowtheir application in a physiologically-compatible solution, such asbuffered isotonic saline. Water-soluble coatings may form thin films,but more preferably form three-dimensional gels of controlled thickness.

It is especially preferable in cases involving implants that the coatingformed be biodegradable, so that it does not have to be retrieved fromthe body. Biodegradability, in this context, is the predictabledisintegration of an implant into small molecules which will bemetabolized or excreted, under the conditions normally present in aliving tissue.

Preferred monomers are the photopolymerizable, biodegradable,water-soluble macromers described by Hubbell et al. in U.S. Pat. No.5,410,016, the teachings of which are incorporated herein. Thesemonomers are characterized by having at least two polymerizable groups,separated by at least one degradable region. When polymerized in water,they form coherent gels which persist until eliminated byself-degradation. In the most preferred embodiment, the macromer isformed with a core of a polymer which is water soluble andbiocompatible, such as the polyalkylene oxide polyethylene glycol,flanked by hydroxy acids such as lactic acid, having coupled theretoacrylate groups. Preferred monomers, in addition to being biodegradable,biocompatible, and non-toxic, will also be at least somewhat elasticafter polymerization or curing. Elasticity, or repeatablestretchability, is often exhibited by polymers with low modulus. Brittlepolymers, including those formed by polymerization of cyanoacrylates,are not generally effective in contact with biological soft tissue.

It has been determined that monomers with longer distances betweencrosslinks are generally softer, more compliant, and more elastic. Thus,in the polymers of Hubbell, et al., increased length of thewater-soluble segment, such as polyethylene glycol, tends to give moreelastic gel, and these tend to adhere better, especially understretching (as when applied to lung). Molecular weights in the range of10,000 to 35,000 of polyethylene glycol are preferred for suchapplications, although ranges from 3,000 to 100,000 are useful.

In the discussion below and the examples, monomers of this kind, alsocalled macromers, are often designated by a code of the form xxKZn."xxK" represents the molecular weight of the backbone polymer, which ispolyethylene glycol unless otherwise stated, in thousands of daltons. Zdesignates the biodegradable linkage, where L is for lactic acid, G isfor glycolic acid, C is for caprolactone, and TMC is fortrimethylenecarbonate. N is the average number of degradable groups inthe block. The molecules are terminated with acrylic acid groups, unlessotherwise stated; this is sometimes also indicated by the suffix A2.

INITIATORS

The term "initiator" is used herein in a broad sense, in that it is acomposition which under appropriate conditions will result in thepolymerization of a monomer. Materials for initiation may bephotoinitiators, chemical initiators, thermal initiators,photosensitizers, co-catalysts, chain transfer agents, and radicaltransfer agents. All initiators known in the art are potentiallysuitable for the practice of the priming technique. The criticalproperty of an initiator is that the polymerization will not proceed ata useful rate without the presence of the initiator.

The "priming" initiator must adhere sufficiently to the surface to becoated to provide a local source of initiation of the reaction with theparticular monomers to be applied. The initiator must also not be toxicwhen used in biologically-related applications, at least in the amountsapplied. The initiator is preferably a photoinitiator. In discussingphotoinitiators, a distinction may be drawn between photosensitizers andphotoinitiators--the former absorb radiation efficiently, but do notinitiate polymerization well unless the excitation is transferred to aneffective initiator or carrier. Photoinitiators as referred to hereininclude both photosensitizers and photoinitiators, unless otherwisenoted.

Photoinitiators provide important curing mechanisms for additionpolymerization, and especially for curing of ethylenically-unsaturatedcompounds, such as vinylic and acrylic-based monomers. Any of thephotoinitiators found in the art may be suitable, if they adhere to theparticular surface. Examples of photo-oxidizable and photo-reducibledyes that may be used to initiate polymerization include acridine dyes,for example, acriblarine; thiazine dyes, for example, thionine; xanthinedyes, for example, rose Bengal, and phenazine dyes, for example,methylene blue. Other initiators include camphorquinones andacetophenone derivatives. Photoinitiation is a preferred method ofpolymerizing the coatings and adhesives of the invention.

The choice of the photoinitiator is largely dependent on thephotopolymerizable regions. For example, when the macromer includes atleast one carbon-carbon double bond, light absorption by the dye causesthe dye to assume a triplet state, the triplet state subsequentlyreacting with the amine to form a free radical which initiatespolymerization. In an alternative mechanism, the initiator splits intoradical-bearing fragments which initiate the reaction. Preferred dyesfor use with these materials include eosin dye and initiators such as2,2-dimethyl-2-phenylacetophenone, 2-methoxy-2-phenylacetophenone,Darocur™ 2959, Irgacurep™ 651 and camphorquinone. Using such initiators,copolymers may be polymerized in situ by long wavelength ultravioletlight or by light of about 514 nm, for example.

A preferred photoinitiator for biological use is Eosin Y, which absorbsstrongly to most tissue and is an efficient photoinitiator.

It is known in the art of photopolymerization to use a wavelength oflight which is appropriate for the activation of a particular initiator.Light sources of particular wavelengths or bands are well-known.

Thermal polymerization initiator systems may also be used. Systems thatare unstable at 37° C. and initiate free radical polymerization atphysiological temperatures include, for example, potassium persulfate,with or without tetramethyl ethylenediamine; benzoyl peroxide, with orwithout triethanolamine; and ammonium persulfate with sodium bisulfite.Other peroxygen compounds include t-butyl peroxide, hydrogen peroxideand cumene peroxide. As described below, it is possible to markedlyaccelerate the rate of a redox polymerization by including metal ions inthe solution, especially transition metal ions such as the ferrous ion.It is further shown below, that a catalysed redox reaction can beprepared so that the redox-catalysed polymerization is very slow, butcan be speeded up dramatically by stimulation of a photoinitiatorpresent in the solution.

A further class of initiators is provided by compounds sensitive towater, which form radicals in its presence. An example of such amaterial is tri-n-butyl borane, the use of which is described below.

REDOX INITIATORS

Metal ions can be either an oxidizer or a reductant in systems includingredox initiators. For example, in some examples below, ferrous ion isused in combination with a peroxide to initiate polymerization, or asparts of a polymerization system. In this case the ferrous ion isserving as reductant. Other systems are known in which a metal ion actsas oxidant. For example, the ceric ion (4+ valence state of cerium) caninteract with various organic groups, including carboxylic acids andurethanes, to remove an electron to the metal ion, and leaving aninitiating radical behind on the organic group. Here the metal ion actsas an oxidizer. Potentially suitable metal ions for either role are anyof the transition metal ions, lanthanides and actinides, which have atleast two readily accessible oxidation states. Preferred metal ions haveat least two states separated by only one difference in charge. Ofthese, the most commonly used are ferric/ferrous; cupric/cuprous;ceric/cerous; cobaltic/cobaltous; vanadate V vs. IV; permanganate; andmanganic/manganous.

CO-INITIATORS AND COMONOMERS

Any of the compounds typically used in the art as radical generators orco-initiators in photoinitiation may be used. These include co-catalystsor co-initiators such as amines, for example, triethanolamine, as wellas other trialkyl amines and trialkylol amines; sulfur compounds;heterocycles, for example, imidazole; enolates; organometallics; andother compounds, such as N-phenyl glycine.

Co-monomers can also be used. They are especially useful when themonomer is a macromolecule, as in Example 1 below; in that case, any ofthe smaller acrylate, vinyl or allyl compounds can be used. Comonomerscan also act as accelerators of the reaction, by their greater mobility,or by stabilizing radicals. Of particular interest are N-vinylcompounds, including N-vinyl pyrrolidone, N-vinyl acetamide, N-vinylimidazole, N-vinyl caprolactam, and N-vinyl formamide.

SURFACTANTS, STABILIZER, AND PLASTICIZERS

Other compounds can be added to the initiator and/or monomer solutions.Surfactants may be included to stabilize any of the materials, eitherduring storage or in a form reconstituted for application. Similarly,stabilizers which prevent premature polymerization may be included;typically, these are quinones, hydroquinones, or hindered phenols.Plasticizers may be included to control the mechanical properties of thefinal coatings. These are also well-known in the art, and include smallmolecules such as glycols and glycerol, and macromolecules such aspolyethylene glycol.

DRUGS

Biologically active materials may be included in any of the coatingsdescribed herein, as ancillaries to a medical treatment (for example,antibiotics) or as the primary objective of a treatment (for example, agene to be locally delivered). A variety of biologically activematerials may be included, including passively-functioning materialssuch as hyaluronic acid, as well as active agents such as growthhormones. All of the common chemical classes of such agents areincluded: proteins (including enzymes, growth factors, hormones andantibodies), peptides, organic synthetic molecules, inorganic compounds,natural extracts, nucleic acids, lipids and steroids, carbohydrates,glycoproteins, and combinations thereof.

SURFACES TO BE TREATED

Surfaces to be coated include biologically-related surfaces of allkinds. In particular, any tissue or cell surface is contemplated, aswell as the surface of a device to be used in the body or in contactwith bodily fluids. A coating may be applied to the surface of any ofthese, in an amount effective to improve tenacity of adherence.Moreover, the technique may be used to adhere surfaces to each other.For example, wounds in living tissue may be bonded or sealed using thistechnique or preformed medical appliances may be bonded to tissue.Examples of such applications are grafts, such as vascular grafts;implants, such as heart valves, pacemakers, artificial corneas, and bonereinforcements; supporting materials, such as meshes used to seal orreconstruct openings; and other tissue-non-tissue interfaces. Aparticularly important class of tissue surfaces is those which arefriable, and therefore will not support sutures well. Adherent coatingscan seal the suture lines, support sutured areas against mechanicalstress, or substitute entirely for sutures when mechanical stress islow. Examples of such situations include vascular anastomosis, nerverepair, repair of the cornea or the cochlea, and repair of the lung,liver, kidney and spleen.

The priming technique can also be used on non-tissue surfaces ingeneral, where useful bonds may be formed between similar or dissimilarsubstances, and solid or gel coatings are tightly adhered to surfaces.In particular, a pre-formed gel, or other fragile material, may betightly adhered to a supporting material by this method.

The priming method of this invention is advantageous because it can beused to coat and or to bond together any of a wide variety of surfaces.These include all surfaces of the living body, and surfaces of medicaldevices, implants, wound dressings and other body-contacting atrificialor natural surfaces. These include, but are not limited to, at least onesurface selected from the following: a surface of the respiratory tract,the meninges, the synovial spaces of the body, the peritoneum, thepericardium, the synovia of the tendons and joints, the renal capsuleand other serosae, the dermis and epidermis, the site of an anastomosis,a suture, a staple, a puncture, an incision, a laceration, or anapposition of tissue, a ureter or urethra, a bowel, the esophagus , thepatella, a tendon or ligament, bone or cartilage, the stomach, the bileduct, the bladder, arteries and veins; and devices such as percutaneouscatheters (e.g. central venous catheters), percutaneous cannulae (e.g.for ventricular assist devices), urinary catheters, percutaneouselectrical wires, ostomy appliances, electrodes (surface and implanted),and implants including pacemakers, defibrillators, and tissueaugmentations.

BIOLOGICALLY ACTIVE AGENTS

Biologically active substance can be incorporated into the polymer.Examples of useful biologically active substances include proteins(including enzymes, growth factors, hormones and antibodies), peptides,organic synthetic molecules including antibiotics, inorganic compounds,natural extracts, nucleic acids including genes, antisense nucleotides,and triplex forming agents, lipids and steroids, carbohydrates,including hyaluronic acid and heparin, glycoproteins, and combinationsthereof.

Methods of Treatment

Generally, any medical condition which requires a coating or sealinglayer may be treated by the methods described herein to produce acoating with better adherence. In the examples below, lung tissue issealed against air leakage after surgery using the priming technique.Likewise, wounds may be closed; leakage of blood, serum, urine,cerebrospinal fluid, air, mucus, tears, bowel contents or other bodilyfluids may be stopped or minimized; barriers may be applied to preventpost-surgical adhesions, including those of the pelvis and abdomen,pericardium, spinal cord and dura, tendon and tendon sheath. Thetechnique may also be useful for treating exposed skin, in the repair orhealing of incisions, abrasions, burns, inflammation, and otherconditions requiring application of a coating to the outer surfaces ofthe body. The technique is also useful for applying coatings to otherbody surfaces, such as the interior or exterior of hollow organs,including blood vessels. In particular, restenosis of blood vessels orother passages can be treated. The techniques can also be used forattaching cell-containing matrices, or cells, to tissues, such asmeniscus or cartilage.

GENERAL SEALING OF BIOLOGICAL TISSUES

As shown in the examples below, the priming method of polymerization isespecially effective in the sealing of biological tissues to preventleakage. However, the examples also demonstrate that a degree of sealingcan be achieved with photopolymerizable systems without the improvementof priming the tissue with photopolymerizing initiator. There have beennumerous attempts to reliably seal tissue with a number of materials,including most prominently cyanoacrylates and fibrin glues. None ofthese prior art techniques has been entirely satisfactory.Cyanoacrylates, which polymerize on exposure to moisture, and can beaccelerated by amines, are very "stiff" once polymerized. If there isany motion of the biological material, they tend to crack, and losetheir self-cohesion and/or their adherence to tissue. Fibrin glues canbe difficult to prepare, especially in the currently-preferredautologous version; they require enzymatic or toxic chemical means to begelled or crosslinked; and they are rapidly degraded by native enzymes.

The range of uses of sealing or bonding materials in the body is verylarge, and encompasses many millions of potential uses each year. Incardiovascular surgery, uses for tissue sealants include bleeding from avascular suture line; support of vascular graft attachment; enhancingpreclotting of porous vascular grafts; stanching of diffuse nonspecificbleeding; anastomoses of cardiac arteries, especially in bypass surgery;support of heart valve replacement; sealing of patches to correct septaldefects; bleeding after sternotomy; and arterial plugging. Collectively,these procedures are performed at a rate of 1 to 2 million annually. Inother thoracic surgery, uses include sealing of bronchopleural fistulas,reduction of mediastinal bleeding, sealing of esophageal anastomoses,and sealing of pulmonary staple or suture lines. In neurosurgery, usesinclude dural repairs, microvascular surgery, and peripheral nerverepair. In general surgery, uses include bowel anastomoses, liverresection, biliary duct repair, pancreatic surgery, lymph noderesection, reduction of seroma and hematoma formation, endoscopy-inducedbleeding, plugging or sealing of trocar incisions, and repair in generaltrauma, especially in emergency procedures. In plastic surgery, usesinclude skin grafts, burns, debridement of eschars, and blepharoplasties(eyelid repair). In otorhinolaryngology (ENT), uses include nasalpacking, ossicular chain reconstruction, vocal cord reconstruction andnasal repair. In opthalmology, uses include corneal laceration orulceration, and retinal detachment. In orthopedic surgery, uses includetendon repair, bone repair, including filling of defects, and meniscusrepairs. In gynecology/obstetrics, uses include treatment of myotomies,repair following adhesiolysis, and prevention of adhesions. In urology,sealing and repair of damaged ducts, and treatment after partialnephrectomy are potential uses. Sealing can also be of use in stoppingdiffuse bleeding in any of a variety of situations, including especiallytreatment of hemophiliacs. In dental surgery, uses include treatment ofperiodontal disease and repair after tooth extraction. Repair ofincisions made for laparoscopy or other endoscopic procedures, and ofother openings made for surgical purposes, are other uses. Similar usescan be made in veterinary procedures. In each case, appropriatebiologically active components may be included in the sealing or bondingmaterials.

APPLICATION TECHNIQUES AND DEVICES

Both priming and polymer addition may be accomplished by simple drippingof material onto the surface to be coated. This can be accomplishedusing common devices such as a syringe, a pipet, or a hose, depending onscale. More uniform applications may be obtained using an applicator,such as a brush, a pad, a sponge, a cloth, or a spreading device such asa finger, a coating blade, a balloon, or a skimming device. These mayfurther be used to rub the surface to improve penetration of the primeror the monomer, or to mix primer and monomer in situ on the surface. Inlarge-scale applications, fluid layers may be applied with large-scalecoating machinery, including roll coaters, curtain coaters, gravure andreverse gravure devices, and any of the coating devices known in theart. Sprayers may be used at any scale, especially for lower-viscosityprimers or polymerizable monomer layers.

Application techniques and devices may be combined, as in applying fluidfrom a syringe, and then rubbing it into the surface with a finger tip.Such operations may be repeated, as in applying drops of priminginitiator; rubbing these into the surface with a brush; repeating thisoperation; adding monomer solution; rubbing it in; and finally applyingadditional layers of monomer before or during the application of curingmeans, such as light, heat, or slow release of peroxide radicals.

An additional application means which is required in many coatingtechniques described herein, and in particular in the preferred coatingmethod which uses photoinitiation to cure the monomer, is a lightsource. For large-scale application, flood lamps and similar devices areuseful. In small, localized applications, such as tissue sealing andcoating, it may be preferable to use a localized source such as a fiberoptic or light guide, which can project radiation of the appropriatewavelength onto the site to be treated to cause polymerization of themonomer. Also, a light emitter could be carried on a device, as aminiature bulb. A focused beam from a remote source could be suitableif, for example, the surface was exposed. In exposed surfaces, it ispossible that ambient light could be sufficient to polymerize thecoating, especially at high initiator levels.

Each of the applications means can be separate, so that a kit ofapplication means could contain, for example, one or more reservoirs,one or more pads or brushes, and if required at least one light guide.The application means could also be combined in whole or in part. Forexample, a dripping device, such as a tube, could be combined with aspreading device, such as a brush. These could further be combined witha light guide. Such combination devices are especially desirable intreatment of living organisms, and especially humans, to maximize thesimplicity of a procedure and the probability of correctly conductingit.

Thus, a combination device for conducting a primed photopolymerizationin a biological or medical setting will contain at least the followingelements:

a) one or more means for applying a fluid to a surface, selected fromdripping means, irrigating means, spraying means, applicator pad meansincluding brushes, balloons, fabrics and foams, and rigid surfaces, suchas spatulas, for applying paste-like or highly viscous fluids;

b) one or more optional means for spreading or rubbing a fluid onto asurface, which may be brushes, pads, rigid or semi-rigid protuberances,and which may be the same or different as the fluid-application means;

c) one or more reservoirs, or connecting conduits for receiving thecontents of reservoirs into the device, for a primer, a monomersolution, and/or a combination thereof;

d) light-delivery means, which may be a fiber optic, a light guide, afocused remote beam, or a locally-deployed light source, such as aminiature lamp;

e) a proximal end adapted to be held by the person administering thetreatment, optionally further including means for selection among theone or more application means, spreading means, reservoir means, andlight-delivery means (i.e., switching means); and

f) a distal end or ends, optionally adapted to be sterilizable, fromwhich the one or more fluids are dispensed.

Other options for the device include metering means for the fluids, sothat a controlled amount may be dispensed, or a controlled pressure maybe maintained; feedback devices, such as optical viewers and indicatorsof function; and interlocks to correctly sequence the applicationprocedure, or to insure dispensing of the required amounts of initiator,monomer, and light or other polymerization stimulator.

Many devices and arrangements can be constructed that meet theserequirements. One embodiment of such a device is illustrated in FIGS. 1aand 1b, in which FIG. 1a is a longitudinal schematic cross-section, andFIG. 1b is a view from the proximal end of a two-fluid-one-dispenserversion.

In FIG. 1a, a main shaft 10, of which the distal end is shown, carrieslight from a remote light source (not shown) coupled into an opticalfiber or fibers 12 passing into the shaft through a bushing orstrain-relief member 13 at the proximal end of the device, and throughthe axis of the device to a distal emission element 11. The emissionelement contains appropriate optical elements to distribute the lightonto the site where polymerization is to occur. These may be as simpleas a window, but may include other arrangements known in the art todistribute the light, including diffusers, lenses or gratings, andcollimating stops.

Syringes 47, 48 (see also FIG. 1b) with check valves 21 are provided forthe delivery of fluids via a connector 24 through a bifurcation in thebody extension 20 to a fluid delivery conduit 22, the ends of which areshown. The fluid delivery conduit may have a specialized applicator tip23, such as a spray nozzle, or may be smooth for simple delivery offluid by dripping. The fluid delivery conduit is optionally surroundedby a slidable tube 31 carrying a spreading device 32, which is connectedby a block 33 which slides on the main shaft 10. The sliding block 33slides the telescoping tube 31 on the fluid delivery conduit 22. Theblock is connected by a connecting rod 34 to a trigger mechanism 35,which is used to slide the spreading device 32 either distally of theemission element 23, or proximately of it, depending on the step of thepriming operation. The trigger 35 may also optionally be provided withspring tensioners 36 or latches or detents for controlling position (notillustrated).

A syringe barrel 40 containing a fluid to be delivered 42 is fitted witha plunger 41. The plunger is selectively contactable by a plunger driver44, which may be rotated about the device axis 45 to drive either of thetwo syringes 47, 48 shown in FIG. 1b. The syringes are held on thedevice by a clamp 46.

The plunger driver 44 is connected to a freely sliding rod 57 which canslide into a recess 58 in the device under the influence of slidablehand grip 55, which slides into handle 51. A finger guard 53 is providedfor convenience.

In operation, the device is used as follows. With the spreading device32 retracted to the proximal position, the plunger driver 44 ispositioned over the filled initiator (primer) syringe 47, and bycompressing the slidable portion of the hand grip 55 into the handle 51,fluid is dripped from delivery conduit 22 onto the target area. Then thespreading device is moved to the distal position and is used, bymovement of the device as a whole by the operator, to spread theinitiator priming solution over the entire target area. Alternatively,the spreading device may be in the distal position during primerdelivery, so that the fluid is distributed by it.

Next, the spreading device is optionally retracted, and the driver 44 ismoved to drive syringe 48, which contains a solution with monomer,initiator, carrier amine, and other ingredients. The monomer solution isdripped onto the target region, the spreader is advanced, and themonomer is rubbed into and distributed on the surface. Optionally, thespreader is retracted and further monomer is applied to the surface,optionally with the aid of the spreader, to form a thicker coat.Alternatively, the spreader may be in the distal position throughoutdelivery, so that the fluid is distributed by it.

Finally, the spreader is retracted, and the light source is activated todeliver light to emission element 11 to polymerize the coating on thesurface of the tissue. Optionally, further monomer solution can bedelivered during the emission of light to build up additional thicknessFor this reason, both the delivery tube 22 and the main shaft 10 arepreferably opaque to the light being used. This is conveniently achievedby constructing these elements of metal, such as standard syringe needletubing. If the monomer solution is sensitive to room light, then themonomer syringe 48 should also be shielded or made of opaque material,and the monomer delivery path elements 21, 24 and 20 should likewise beopaque to the radiation wavelengths which initiate polymerization in theparticular monomer/initiator combination. The rest of the device is madeof any suitable material, such as a medical grade plastic. The device asa whole, or particular parts thereof such as the fluid dispensingpathway or the spreader, may be disposable.

In another embodiment, not illustrated, the elements 44, 55, 57 and 58are omitted. The syringe plungers 41 are then exposed, and are drivendirectly by thumb pressure.

In an alternative embodiment, an additional trigger may be provided toconnect to means for delivering a controlled amount of fluid with eachsqueeze of the trigger. Suitable ratchet means are known in the art; onesuch means is disclosed in co-pending application U.S. Ser. No.08/036,128. In an alternative embodiment, separate fluid pathways may beprovided for each of the two fluids. The separate pathways may beparallel or concentric. In the former case, separate spreading elementsmay be provided for each pathway.

An embodiment of a delivery device incorporating both of these featuresis shown in FIG. 2. The device operates similarly to the device in FIG.1, but uses a pumping mechanism composed of two pairs of one-way checkvalves, of which one pair is shown as 145 and 146, to pull fluid fordelivery out of disposable syringes 136, 137, mounted in the handle 126,and inject the fluid through tubing 128, 129 into parallel deliveryducts terminating at orifices 101. The pumping action is driven by atrigger 107 mounted on a pivot 108. The trigger is linked via aconnecting dowel 109 and a push rod 123 to either of a pair of spring118-loaded pistons 116 by a switchable plate 122, similar in operationto that shown in FIG. 1, which couples to either of the pistons. Thepistons are mounted in a housing 124 and sealed with O-rings 115. Forillumination, an optical fiber 106 emitting through a window 104 with adiffuser 105, is connected through the body of the device to an opticalconnector 135 which delivers light from a remote source. The orifices,window and diffuser are carried in an end cap 102. Other featuresillustrated are similar to the device of FIG. 1, and include a mainshaft 103), brush 138, and sliding brush shaft 140 with handle 141, towhich the brush is removably attached with shrink-wrap 139.

Advantages of the device of FIG. 2 are the ability to deliver a knownvolume with each stroke of the trigger, and ease of changing syringes136, 137 for replenishing reagent supply if required. As illustrated,one of the fluid delivery paths 128 is constructed from black flexibletubing, to avoid exposure of reactive monomer to light before delivery.

Another embodiment of apparatus for conducting primedphotopolymerization, device 140, is illustrated in FIG. 4. Device 140 issimilar to devices described above and illustrated in FIGS. 1a-2 in thatit includes a proximal portion adapted to be held by the hand of anoperator of the device, a distal portion including an apertures fordispensing fluid at a treatment site, and a conduit arranged to connecta source of fluid to the aperture at the distal portion. More than oneaperture and conduit are provided according to preferred embodiments,and device 140 is designed to allow particularly effective dispensing,independently or together, of at least two fluids to a target area viasimple, one-hand operation of a right-handed or left-handed operator.

Device 140 includes a handle assembly 142 including a rear handleassembly 144 and a front handle, or trigger, 146 mounted so as to pivotabout a pin 148 that passes through outer walls of rear handle assembly144. Rear handle assembly 144 extends upwardly to define a cavityincluding (as described more fully below with reference to FIGS. 5 and6), a set of recesses in which a set of lead racks 150 and 152 fordriving plunger drivers are carried (lead rack 152 is hidden in FIG. 4),a ratchet mechanism arranged to drive lead racks 150 and 152, aswitching mechanism arranged to operably connect trigger 146 with eitherof the lead racks, and a set of sleeves including displays 154 and 155(hidden) that visually indicate the setting of the switching mechanism,that is, that indicate which of lead racks 150 or 154 are operablyconnected to trigger 146. A thumb wheel 156 is rotatable between firstand second, detented positions, respectively, in which trigger 146 isoperably connected to lead rack 150 or lead rack 152, respectively. Ahousing arrangement including a top cover 158 and a front cover 160houses the ratchet mechanism, lead rack recesses, and portions of thesleeves carrying the displays. Front cover 160 houses gears that define,in part, the switching mechanism. The device is assembled with standardfasteners.

An upper, removable assembly 162 is removably connected to handleassembly 142 via sliding engagement locked by a latch 163 (describedmore fully below). Upper assembly 162 includes a syringe housing unit164 including one or more recesses designed to carry one or moresyringes. Preferably, two syringes (syringe 166 only is shown in FIG. 4)are mounted in recesses of the syringe housing unit during use. Plungerdrivers 170 and 172 (172 is hidden) fastened to, or integral with theproximal ends of lead racks 150 and 152, respectively, can clamp syringeplungers 174 and 176, respectively, thereby operably connecting trigger146 with either of the plungers.

Upper assembly 162 includes a main shaft 178 extending distally from thedistal end of syringe housing unit 164. As in the embodimentsillustrated in FIGS. 1a-2 and described above, central shaft 178includes, at its distal end, an electromagnetic emission element 180 andone or more applicator tips, or outlets, for application of deliveringfluid to a target area. In the embodiment illustrated, two applicatortips 186 and 188 (188 is hidden) are in fluid communication withsyringes in unit 164 via conduits (hidden) extending from syringerecesses in syringe housing unit 164 through shaft 178. According to oneembodiment, main shaft 178 and the applicator tips are made of stainlesssteel. According to another embodiment, the shaft and one or bothapplicators are made of a more flexible material. For example, in somesettings it could be safer in terms of avoiding accidental puncture orother damage to tissue to fabricate the applicators of a flexiblematerial such as medical grade plastic. According to another embodiment,main shaft 178 (and components therein, to the extent needed to achieveflexibility) is made of a flexible material and is an articulating shaftwhich can be steerable. The shaft is bendable and rotatable according tothis embodiment.

A brush shaft 190 is coaxial with, and mounted on, main shaft 178 and isslidable proximally and distally thereon. Brush shaft 190 includes, on aferrule 189 at its distal end, a spreading device 192 that can be abrush, pad, or the like, as described above with reference to FIG. 1a.As illustrated, spreading device 192 is a brush that is positioned todepend distally and downwardly from the distal end of brush shaft 190 atan exemplary angle of approximately 30 degrees. Spreading device 192 canbe arranged to project axially, directly downwardly, or can be arrangedin any other manner. Brush shaft 190 can be moved proximately over shaft178 and spreading member 192 thereby positioned proximate the distal end179 of main shaft 190, or moved distally thereby positioning thespreading member at a deployed position, preferably distally of distalend 179 of shaft 178. Limits on travel of brush shaft 190 proximally anddistally on shaft 178, and rotational orientation of the brush shaftrelative to the shaft, can be controlled by a pin 191 extending from theshaft 178 through a longitudinal slot (not shown) in brush shaft 190within which the pin travels when brush shaft 190 is movedlongitudinally relative to shaft 178.

A grip mechanism 194 is designed to allow, at one setting, brush shaft190 to slide easily longitudinally on shaft 178 and to impede, atanother setting, movement of the brush shaft relative to the shaft.Mechanism 194 includes a fixed portion 196 secured to or integral withbrush shaft 190 and a rotatable portion 198 that threadingly engagesfixed portion 196. An expandable element such as an o-ring (hidden)resides between portions 196 and 198 and, when portion 198 is screwedtoward portion 196, the expandable element is squeezed and expandsagainst the outer surface of shaft 178, frictionally engaging the shaft.

According to another embodiment (not illustrated), spreading member 192can be mounted within a sleeve that surrounds shaft 178 and, when urgeddistally or when the surrounding sleeve is urged proximally, is exposed.In such an arrangement, the spreading member can spring outwardly whenexposed and, and, when the member is in its retracted position, theshaft construction can be passed through a passage such as a trocarcannula.

According to a preferred embodiment, electromagnetic radiation emitter180 is an emitter of light and is defined by a window, such as asapphire window, optically coupled, via an optical fiber passing throughshaft 178, syringe housing unit 164, and a flexible cable 200 to asource of light remote from device 140. Cable 200 can terminate in a setof connecters 202 including an optical coupler 204 connectable to asource of light such as a laser, and an electrical coupler 206.Electrical coupler 206 is connectable to an electrical source, and iselectrically connected, via wiring in cable 200, to an electro-opticalswitch mounted in syringe housing unit 164. Electro-optical switches areknown, and in accordance with the invention can be a simple on-offswitch, a timed switch that when activated will cause illumination for apredetermined period of time such as 20 seconds, and the like. Whenconnecters 202 are coupled appropriately to sources of light andelectricity, when button 208 is pressed light exits emitter 180 at thedistal end of shaft 178. When the button is not pressed, emitter 180 isblocked from receiving radiation. Such switches and optical andelectrical connections are known.

Referring to FIG. 5, handle assembly 142 and upper assembly 162 areshown disconnected from each other in partial cross section. Upperassembly 162 can be fastened to lower, handle assembly 142 by engagementof a beveled protrusion 224, typically referred to as a dovetail, withina corresponding slot 226 in upper assembly 162. Upper assembly 162 ispositioned atop the handle assembly, with the front of slot 226 alignedwith the rear of protrusion 224, and moved forward until the rear ofprotrusion 224 abuts the rear of slot 226, whereupon protrusion 228 oflatch 163 mates with indentation 230 of upper assembly 162. Latch 163 isurged upwardly by a spring 232, and can be moved downwardly easily bythe thumb of an operator, allowing upper assembly 162 to be slidrearwardly and removed from handle assembly 142.

The upper and lower assemblies can be detached for a variety of reasons.According to one embodiment, the upper assembly is packaged as asterile, one-use, disposable unit. The upper assembly can include, forexample, a first syringe containing a photoinitiator and a secondsyringe containing a drug admixed with a monomer. The lower assembly canbe reusable, or can be a limited-use unit, and used several or manytimes with various disposable upper assemblies. More than one upperassembly can be used in a single medical procedure where it is desirableto provide different combinations of formulations for slightly differenttherapies. Or, a procedure can be initiated where it will not be knownuntil well into the procedure precisely which of several optionalformulations will be most desirable, and clinical staff can have on handa lower assembly and a plurality of upper assemblies each loaded with adifferent combination of agents.

Trigger 146 pivots about pin 148 and is urged forward, in its restingposition, by spring 210 which also engages the rear handle assembly.When the trigger pivots rearwardly on pin 148 an upper portion of thetrigger above the pin pivots forward. The upper trigger portion includesa slot 212 engaged by a clevis pin 214. Clevis pin 214 is connected to abracket 216 which is connected to a ratchet carriage 218 housing aratchet mechanism (described below), and the trigger is thereby operablylinked to the rachet mechanism. An adjustable screw 220 limits rearwardtravel of ratchet carriage 218. A pin 222, about which thumb wheel 156rotates, inserts into the front portion of the rear handle assembly.Upper, removable assembly 162 includes an electro-optical switch 234controlling passage of light via an optic fiber 236 which passes fromwithin cable 200, through shaft 178, to optical emitter 180, and isactuated by button 208 as described above.

Referring now to FIG. 6, a ratchet mechanism for controlling applicationof fluid from syringes mounted in the syringe housing unit 164 isillustrated in greater detail. The ratchet mechanism is designed tooperate by allowing pawls 238 and 240, respectively, to engage ratchetteeth 242 or 244 of lead rack 150 or 152, respectively, so that whentrigger 146 is squeezed, one of plunger drivers 170 or 172 move forwardto drive one of the syringe plungers. The arrangement can be adapted, aswill be recognized by those of ordinary skill in the art, so that bothof pawls 238 and 240 simultaneously engage teeth 242 and 244.

With reference to FIG. 7 in conjunction with FIG. 6, operation of theratchet mechanism will be described. Thumb wheel 156 is rotated on pin222 between first and second positions defined by limits of the travelof a fixed pin 246 in a slot 248 of defined arcuate dimension. A detentmechanism (not shown) is positioned within handle assembly 144 andengages thumb wheel 156 at each of the two positions. Thumb wheel 156includes teeth at its perimeter that mesh with teeth of drive gears 250and 252. Drive gears 250 and 252 are secured to or integral with sleeves254 and 256, respectively, which surround lead racks 150 and 152,respectively, from the drive gears rearward (proximally) toga point justpast pawls 238 and 240. Each of the sleeves 254 and 256 includes anopening, or window aligned longitudinally with adjacent pawl 238 or 240,respectively. Each opening is positioned radially, and has an arcuatedimension such that, when the thumb wheel is in one position the slot isoriented so as to expose the teeth to the pawl, and when the thumb wheelis moved to the other position the slot is rotated away from the pawland the sleeve blocks the pawl from engagement with the teeth. Forexample, when thumb wheel 156 is rotated clockwise (as viewed from thefront as in FIG. 7) to the limit allowed by arcuate slot 248, sleeve 254is rotated by drive gear 250 to a position in which the window in sleeve254 exposes pawl 238 to ratchet teeth 242 of lead rack 150, while sleeve256 is rotated by drive gear 252 to a position in which the window insleeve 256 rotates away from pawl 240, and sleeve 256 blocks pawl 240from engagement with teeth 244 of lead rack 152. In this position, whentrigger 146 is squeezed and pivots on pin 148, it drives bracket 216forward via clevis pin 214, which drives ratchet carriage 218 forward,which causes pawl 238 to engage teeth 242 and thereby to drive lead rack150 and plunger driver 170 forward. Plunger driver 172 is not drivenforward. When thumb wheel 156 is rotated counterclockwise to its limitand the trigger squeezed, the opposite occurs, namely, plunger driver172 is driven forward and plunger driver 170 is not. Other arrangementsfor operably linking the thumb wheel (or other switch) to the sleeveswould be apparent to those of ordinary skill, and can be constructed inaccordance with the invention.

Sleeves 254 and 256 can carry displays 154 and 155, respectively, thatare visible through windows 258 and 260, on respective sides of the topcover 158 of the handle assembly 142. The displays can be coordinated torotate in and out of the windows so that, depending upon the position ofthumb wheel 156, and which of the lead racks is engagable by the ratchetmechanism, indication is visibly made as to which syringe is operablylinked to the active lead rack, that is, which component will bedispensed upon movement of trigger 146.

Each of lead racks 150 and 152 is rotatable about its axis into a firstorientation in which its plunger driver 170 or 172, respectively, isorientated to engage the plunger of a syringe carried by syringe housingunit 164 and its teeth, 242 or 244, respectively, are positioned toengage pawl 238 or 240, respectively, and into a different orientationin which its plunger driver is in a position of disengagement from asyringe plunger and its teeth are rotated out of engagement with theadjacent pawl. As illustrated in FIG. 6, both lead racks are positionedto engage a syringe plunger and be engaged by a pawl.

FIG. 8 is a partial cross section of upper, removable assembly 162, witha proximal portion only of syringe 174 illustrated. Syringe housing unit164 includes individual syringe housings 260 and 262 each including arearward-facing opening into which a syringe can be inserted. Thesyringe housings are of different sizes, as illustrated, but can be ofthe same size. Housing 260 includes, at its distal end, a fluid-tightconnection such as a Luer-lock™ fitting 264 engagable by the distal endof syringe 174. Fitting 264 is connected to a conduit 266 which extendsthrough main shaft 178 and terminates in applicator tip 186. Housing 262includes also a Luer-lock™ fitting 268 connected to a conduit 270extending through main shaft 178 and terminating in applicator tip 188.

As illustrated, lead rack 152 is positioned rotationally such thatplunger driver 172 is not aligned with housing 262. In this position asyringe can be removed from, or inserted into, syringe housing 262.Additionally, in this position teeth 244 do not engage pawl 240regardless of the position of thumb wheel 156, thus lead rack 152 canfreely be moved forward or rearward to align plunger driver with theproximal end of a syringe in housing 262. Plunger driver 172 includes arecess 271 into which the proximal end of a syringe plunger fits snuglywhen the lead rack is rotated and the recess of the driver is movedlaterally over the plunger end. Recess 272 is shaped so as not to allowa syringe plunger to escape proximally. That is, the plunger driver canbe removed from the plunger only by rotating the lead rack and slidingthe driver laterally away from the plunger.

Syringe 166 is positioned in syringe housing 260 (although the proximalend only of the syringe is shown) with lead rack 150 (hidden) positionedrotationally such that plunger driver 170 engages the proximal end ofplunger 174. In this position, teeth 242 of lead rack 150 are orientedfacing pawl 238 and, if thumb wheel 156 is rotated clockwise (withreference to the orientation of FIG. 7), when trigger 146 is squeezedteeth 242 are engaged by pawl 238, plunger driver 170 is drivendistally, causing depression of plunger 174 into syringe 166 anddelivery of the content of syringe 166 to applicator tip 186. As can beseen, when syringes are mounted in both syringe housings 260 and 262,Thumb wheel 156 can be rotated from a first, clockwise position in whichactuation of trigger 146 causes the content of a syringe in housing 260to be delivered to applicator tip 186, and a second, counterclockwiseposition in which trigger actuation delivers the content of a syringe inhousing 262 to applicator tip 188.

Device 140 can be constructed according to several embodiments notillustrated. According to one, optic fiber-supplying cable 200 isconnected to handle assembly 144, rather than to syringe housing 164,and when upper assembly 162 is coupled to lower assembly 142, an opticalconnection is made between the assemblies so as to connect emitter 186to the light source. According to other embodiments, thumb wheel islocated just above rear handle 144, and light button 208 is replacedwith an auxiliary trigger in front of trigger 146 for alternate access.These and other modifications can be made. The device is fabricated fromstandard medical grade steel and/or plastic.

Referring now to FIG. 9, a hand held arrangement for delivery ofmaterial for primed photopolymerization, or other material isillustrated in cross section. A housing component 272 includes a syringehousing 274 for receiving a syringe 276. Housing 274 includes, at itsdistal end, a Luer-lock™ fixture 277 fluidly connected via a conduit 278to a distal tip 280. Syringe 276 can be placed in housing 274 andsecured thereto via Luer-lock™ fixture 277, and when plunger 282 of thesyringe is depressed, the content of the syringe is delivered throughdistal delivery tip 280. Alternatively, the housing component 272 can befitted with a distal applicator 284 including a cavity 286 into which adistal portion 288 of housing component 272 fits frictionally via, forexample, a standard Luer™ type fitting. Cavity 286 is fluidly connected,via conduit 290, to a distal tip 292 located, as illustrated, within abrush 294. This extends the delivery pathway distally, and provides abrush as a spreading element. The spreading brush can be replaced with avariety of devices such as pad, etc., as described above.

FIG. 10 illustrates an assembly 296 defined by the assembled componentssyringe 276, housing component 272 and extender 284 including brush 294.

According to another embodiment, syringe 276 is coupled directly toextender 284 carrying brush 294, without housing component 272.Applicator component 284 includes, at its proximal end, a Luer-lock™fitting 298 that can be coupled to the distal end of syringe 276. Thus,a relatively longer device as illustrated in FIG. 10 and includingsyringe housing 274, or a relatively shorter device defined byapplicator 284 coupled directly to syringe 276, can be assembled.

Referring now to FIG. 11, a schematic illustration of use of the deviceillustrated in FIG. 10 is presented. As illustrated, device 296 is usedto apply to a surface 300 a photopolymerizable material such amonomer/initiator formulation 302. After application of material 302 tosurface 300 (via dripping from the applicator tip 292 or introduction ofthe material within brush 294 followed by direct transfer to surface 300from the brush), material 302 can be spread or positioned accordingly bybrush 294. Then, a radiation or light wand 304 having a distal,light-emitting end 306 can be brought into position and actuated viadepression of an electro-optic switch 308, whereupon photopolymerizablematerial 302 is polymerized or crosslinked, optionally hardened. Wand304 is connected to optical end electrical couplings 202.

In all embodiments of devices for application of material, any componentdescribed herein, in any formulation or combination, or any othercomponent known to those of skill in the art can be delivered via thedevice Preferably, the device is loaded with an initiator, monomer,drug, co-initiator, co-monomer, surfactant, stabilizer, and/orplasticizer as described herein, but it is to be understood that thedevices of the invention can be used with other compositions. Of course,according to preferred embodiments components of the invention aresterile or sterilizable, that is, able to be readily sterilized andadapted to be used in a medical setting.

PACKAGING

The materials for making the coating can be packaged in any convenientway, and may form a kit, alone or together with the application device.The reactive monomers are preferably stored separately from theinitiator, unless they are co-lyophilized and stored in the dark, orotherwise maintained unreactive. A convenient way to package thematerials is in three vials (or prefilled syringes), one of whichcontains concentrated initiator for priming, the second of whichcontains reconstitution fluid, and the third containing dry orlyophilized monomer. Dilute initiator is in the reconstitution fluid;stabilizers are in the monomer vial; and other ingredients may be ineither vial, depending on chemical compatibility. If a drug is to bedelivered in the coating, it may be in any of the vials, or in aseparate container, depending on its stability and storage requirements.

It is also possible, for a more "manual" system, to package some or allof the chemical ingredients in pressurized spray cans for rapiddelivery. If the monomer is of low enough viscosity, it can be deliveredby this route. A kit might then contain a spray can of initiator; aspray can or dropper bottle of monomer, initiator and other ingredients;and an optional spreading or rubbing device. If the monomer andinitiator system are designed to polymerize under the influence ofnatural or operating room light, possibly with the supplement of achemical initiator or carrier such as a peroxygen compound, then thetechnique could be suitable for field hospital or veterinary situations.

EXAMPLES EXAMPLE 1

Relative adhesion of coating to primed and unprimed surfaces.

Fresh pig lung was primed in one area with a solution of photoinitiator(Eosin Y, 1 mg/mL (1000 ppm) in normal saline) and in another area withnormal saline (prior art control). Excess fluid was removed by blotting.About 0.5 mL of monomer solution was applied to each spot. The monomerwas polyethylene glycol (35,000 Daltons) terminated with caprolactone(average of 3.3 caprolactone groups per polyethylene glycol molecule)and capped with acrylic acid, essentially as described in Hubbell et al.The monomer solution contained 15% monomer (w/w), 90 mM triethanolamine,20 ppm (w/w) Eosir, and 5 microliters/mL vinylpyrrolidone (v/v). Thesamples were irradiated with green light until cured (40 sec. at 100mW/cm²) into a firms transparent gel. Initial adherence was seen in bothprimed and control spots, although the primed spots had better overalladherence.

The lung was connected to a pressure-controlled inflation apparatus, andsubjected to chronic fatigue for 1 hour of pneumatic inflation pressuresat 25 to 30 cm of water, in 6 second cycles. This was designed tosimulate the effects of breathing. After the fatigue test, the primedgel spots were still adherent, but the control gel spots could easily belifted from the lung surface with forceps. Thus, adhesion under chronicstress was better with priming before polymerization.

EXAMPLE 2

Sealing of wedge resection of lung.

In lung operations, it is common to make a "wedge resection" to removediseased areas. A combination stapler/cutter is used to simultaneouslycut and staple along one side of the wedge to be removed, and is thenused to staple and cut the other side so that a wedge-shaped piece oflung is removed, while the remaining lung is simultaneously stapledclosed. Despite a high staple density, the staple lines are prone toleak air, which can produce severe complications in a patient undergoingsuch an operation.

Frozen-thawed pig lungs were wedge-resectioned, using a ProxiMate™ TLC55 reloadable linear cutter/stapler (Ethicon; Somerville, N.J.). Everysecond staple was omitted from the outer staple lines in the cassette toreliably induce leaks. Lungs were inflated with air to a pressure of 40cm H₂ O, and leaks were observed by pushing the stapled area just underthe surface of a water bath (similar to leak testing of an inner tube).Next, staple lines were primed with 1000 ppm Eosin Y, blotted, andtreated with the macromer mixture of example 1 which was then cured asdescribed.

In a standard test for durability, the lungs were inflated to 20 cmwater pressure for 10 cycles, over a period of 1 minute, and then heldfor 30 seconds at 40 cm water. The primed and sealed lung sectionsshowed no leaks, demonstrating the effectiveness of the priming systemin sealing known leaks.

Finally, pressure was increased in the primed lungs to determine themaximum pressure before leakage. Small leaks were typically seen at 75cm water or above.

EXAMPLE 3

Lap/Shear Strength of Primed and Unprimed Bonds.

Adhesion under shear of gel to rat skin was determined on an Instron™apparatus using standard methods. The biological surface was rat backskin, freshly removed from euthanized animals. It was glued to a glassslide, and treated as described below. A casting chamber was positionedabove the skin, which also contained a gauze mesh which protruded fromthe chamber. Monomer solution was injected into the chamber andpolymerized. The chamber was removed, and the tensile strength of thebond was determined by shearing the lap between the glass slide and thegauze mesh in a standard load cell on the Instron.

Skin treatments included none (control); primed; primed and pre-coatedwith monomer solution by drip; and primed, pre-coated with monomersolution by drip, and rubbed or mixed with a brush. A monomer solutionas in Example 1 was applied, except that the monomer, "8KL5", had asmaller PEG molecule (8000 D), and was extended with lactate groupsrather than caprolactone groups. With unprimed skin, a differentinitiator, Irgacure™ 651 (Ciba Geigy), was also used in the gellingmonomer mixture.

With the non-primed Irgacure® system, average load at failure for 6 to 8samples ranged from 49 grams of force with low-intensity mixing ofmonomer onto the surface, to 84 to 274 g. with rubbing. Similar resultswere obtained with the Eosin catalysed system with no primer (146 gaverage, range 80-220). When the tissue was pre-primed with Eosin, andmonomer solution was thoroughly mixed with a brush, the failure forceincreased to 325 g (range 220-420). Thus priming can quantitativelyimprove early adherence, in addition to its much larger improvement inadherence after flexing.

EXAMPLE 4

Sealing of a bronchus.

A bronchus was stapled and cut during lobectomy by the techniquesdescribed for wedge resectioning. The staple line was coated asdescribed in example 2, likewise preventing or stopping air leaks.

EXAMPLE 5

Sealing of a laceration.

A laceration 2 mm deep by 2 cm long was made on an isolated lung with ascalpel; the scalpel was taped to control the depth of cut. The lung wastested and found to leak. The laceration was primed, filled with monomersolution containing initiator, and the monomer was photopolymerized. Theleak was sealed by this procedure.

EXAMPLE 6

Coating of a medical device.

A length of polyurethane tubing extrusion used for catheter shafts wasdipped into an aqueous solution containing 20 ppm eosin. Excess eosinwas rinsed off with water. The primed tubing was dipped into a solutioncontaining 10% monomer (type 8KL5, as in example 3), 90 mMtriethanolamine, 5 ppm vinylpyrrolidone, and 20 ppm eosin. Excessmonomer was allowed to drip off. The monomer layer on the tubing wasthen photopolymerized to form an adherent gel coating. The adherence wasstrong enough to survive sectioning of the tubing with a razor blade;photomicrography showed complete adherence of the gel to the tubing. Asa prior art control, the shaft was not primed. After dipping theun-primed shaft into the same monomer solution, the coating on the shaftwas photopolymerized. A gel was formed, but failed to adhere to theshaft, and fell off during handling.

EXAMPLE 7

Priming for surface adherence

Two surfaces of Pebax™ polyeteramid were stained with 1000 ppm Eosin Yand rinsed. Polymerizable monomer solution (10% 8KL5 in water containing20 ppm eosin) was placed between the surfaces, and the sandwich wasexposed to green light. Gel formed in the interface and held thesurfaces together. In a control experiment, in which the surfaces werenot primed, polymerization of the monomer occurred but no significantadherence of the surfaces was found.

EXAMPLE 8

Priming of surfaces.

On exposure to 1000 ppm of Eosin Y, surfaces of Teflon™ fluoropolymerand of polyethylene were observed to stain significantly. When monomerwas added to such surfaces, and allowed to stand briefly, gels wereformed on illumination. Adherence seemed inferior to that obtained onpolyurethane.

EXAMPLE 9

Priming of Uterine Horn and Adherence of Gel Layers.

A model system was established for placing of barriers on mammalianuteruses after operations. Freshly excised uterine horns from euthanizedpigs were removed from a saline bath and treated with 1000 ppm Eosin.Controls were not primed. Polymerizable monomer solution as in Example 7was applied to the primed and control areas. Adherence of gel layers tothe primed areas was very firm, while gels on control areas could bedislodged.

EXAMPLE 10

Water-sensitive initiation.

It is known to use tributylborane as a water-sensitive initiator of bulkpolymerization. In this example, it is shown that TBB can serve as aninitiator in interfacial polymerization, and thus as a primer in thepresent invention.

1 M tributylborane (TBB) solution in THF was purchased from Aldrich.Lyophilized 35KL4A2 reactive monomer containing triethanol amine andeosin was made in these laboratories. Polyethylene glycol 400 (PEG 400)was obtained from Union Carbide). Of the lyophilized powder of 35KL4A2,0.5 gram was dissolved in 9.5 grams of PEG 400. The mixture was warmedusing a heat gun up to 40-50° C. to facilitate dissolution. To thissolution, 30 μL of vinyl pyrrolidinone were added as a comonomer.

Using a glass syringe, 2 ml TBB solution were transferred to a sprayer,of the type used with thin layer chromatography plates. A small amountof TBB solution was sprayed on a glass coverslip and the PEG 400solution containing 35KL4A2 was applied on the TBB solution. Animmediate polymerization of the solution was noticed. The polymerizedfilm was insoluble in water indicating crosslinking.

Similar polymerization was carried out on pig lung tissue. A smallamount of TBB solution was sprayed on approximately 3 cm² of lungtissue. A 35KL4A2 solution in PEG was applied on top of the TBBsolution. A small amount of TBB solution was also sprayed on top of themonomer solution. A well adherent film of 35KL4A2 on lung tissue wasnoticed. The polymerized film was elastic and well adherent to thetissue.

In an alternative procedure, application of the TBB initiator to tissuemay be followed by application of monomer solution containing aphotoinitiator, such as 20 ppm eosin. Photopolymerization is then usedto build a thick layer of gel onto the initiated priming layer. Goodadherence is predicted.

EXAMPLE 11

Combination of redox free radical initiation systems withphotoinitiation and/or thermal free radical initiation systems forincreased polymerization speed.

Previous visible light photopolymerization of Focal macromonomers usesthe aqueous eosin Y/triethanolamine photoinitiation system. Thisreaction has been observed to generate peroxides when carried out in thepresence of dissolved oxygen in the buffer. One may exploit thesegenerated peroxides as an additional source of free radical initiatorsfor polymerization using a Fenton-Haber-Weiss style reaction. In aneffort to use these formed peroxides as polymerization initiators,ferrous ion in the form of ferrous sulfate was added to the eosinY/triethanolamine buffer and used in the photopolymerization of Focalmacromonomers. Using an indentation style hardness test, gel stiffnessas a function of illumination time was used as a measure of gel cure.

In an experiment to evaluate the effectiveness of 50 ppm ferrous ion onthe gelation of the Focal macromonomer 8KLS, two buffers were prepared.The first buffer was prepared in deionized (DI) water using 90.4 mMtriethanolamine(TEOA) and pH adjusting to 7.4 with 6 N HCl. The secondbuffer was prepared similarly but with the addition of ferrous sulfatesuch that there would be approximately 50 ppm ferrous ion available.These buffers were used to prepare a 10% (w/v) 8KL5 gelling solutionwith 1 microliter of vinyl pyrrolidinone per ml of gelling solutionadded as a comonomer. These solutions were then divided into gellingsamples and had 20 ppm of eosin Y added to them. These samples were thenilluminated using an all lines Ar laser at a power of 100 mW/cm². Allillumination timepoints were done in triplicate and kept dark untilstiffness testing was performed. In comparing a 10%(w/v) Focalmacromonomer gelling solution with and without 50 ppm of ferrous ionadded, the gel with the added iron gave significantly more cured gelsthan did the gel without iron.

It is further believed that any free radical initiation system,especially aqueous ones, capable of generating soluble peroxides can begreatly enhanced by the addition of soluble metal ions capable ofinducing the decomposition of the formed peroxides.

EXAMPLE 12

Redox-accelerated curing ("dual cure") of primed systems.

A redox-accelerated system was compared to a purely photoinitiatedsystem for priming tissues. The accelerated system was found to beespecially effective in the presence of blood, which attenuates thelight used in photopolymerization. An acute rabbit lung model of sealingof air leaks was used. A thoracotomy was made under anesthesia in theintercostal space of the rabbit. Anesthesia was induced using anintramuscular injection of ketamine-acepromazine. The seventh rib wasremoved to facilitate access to the lungs, and the animal was maintainedon assisted ventilation. A laceration, about 8 mm×2 mm, was made on eachof the middle and lower lobes of the lung. Air and blood leaks wereimmediately apparent. Bleeding was tamponaded using a gauze sponge, andthe site was then rinsed with saline. Some blood remained, and a slowooze of blood and air leakage from the site was still persistent onventilation.

Two formulations were compared. In the first formulation, the primingsolution contained 500 ppm Eosin Y and 90 mM TEOA (triethanolamine) inWFI (water for injection), while the macromer solution contained 15% w/vmacromer (type 35KL4), 20 ppm Eosin Y, 5 mg/ml vinylcaprolactam, and 90mM TEOA in WFI.

The second formulation contained 500 ppm Eosin Y, 15% 35KL4, and 3 mg/mlferrous gluconate in WFI in the primer, and the same macromer solutionas in the first formulation, supplemented with 500 ppm t-butyl peroxide.

Application methods were the same for both formulations, and consistedof application of 1 ml primer with gentle brushing, followed byapplication of 0.5 ml macromer solution by brushing, and thenillumination with blue-green light at 100 mW/(square centimeter) whiledripping an additional 0.5 ml of macromer. Total illumination time was40 sec. Gels were formed on the tissue by both treatments, and the airand blood leakages were sealed.

Acute adhesion of the gel to tissue was rated on a scale of 1 (poor) to4 (excellent). The first formulation scored 1.5, and the second scored3.5. A notable improvement in adherence of the gel to the living lungswas seen with the use of the dual cure system.

EXAMPLE 13

Optimization of iron concentrations.

The objective is to find a redox system which does not instantaneouslygel the macromer, and which can also be cured by light. Various formulaewere prepared, and their polymerization was studied.

A stock monomer solution (solution 1) contained 15% w/w "35KL4"macromer, lot 031395AL, in TEOA buffer (90 mM triethanolamine,neutralized to pH 7.4 with HCl, in water for injection), and 4000 ppm VC(vinylcaprolactam) and 20 ppm eosin Y (photoinitiator). The buffer wasselected to be compatible with dissolved iron.

Iron-monomer solution (solution 2) contained in addition 20 mg/ml offerrous gluconate, 5.8 mg/ml of fructose, and 18 mg/ml of sodiumgluconate.

Peroxide primer (solution 3) contained: 500 ppm eosin in TEOA buffer,plus 5 microliter/ml of 10% tertiary butyl peroxide. An alternativepriming solution (3b) contained in addition 10% 35KL4.

Serial dilutions of one volume of iron monomer with two volumes of stockmonomer were made, and the gelation time, in the absence ofhigh-intensity light, upon addition of 1 volume of priming solution (3)to two volumes of diluted iron monomer was determined. The stock ironmonomer and the 1:3 dilution gelled very rapidly (1-2 seconds), and a1:6 dilution gelled in 3-4 seconds. The 1:9 dilution gelled veryslowly--no rapid gelation, and partial gelation after 1 hour. Furtherdilutions (1:27, 1:81) did not gel for at least one hour.

The formulation with 1:9 dilution, containing about 2.2 mg/ml of ferrousgluconate, was tested for its ability to adhere to excised tissue, andto gel in the presence of blood. Acute adherence was obtained with 1:9iron monomer solution when primed with the basic peroxide primingsolution, but better adherence was found with monomer-containing primingsolution (3b).

In solution, a mixture of monomer solution (0.3 ml) and normal primer(0.13 ml; without peroxide), which polymerized when exposed to intenseargon laser light, would not gel after addition of 2 drops of blood(about 33 mg). However, a mixture of the same volumes of 1:9 ironmonomer, primer 3b, and blood gelled in 5 seconds on exposure to thesame light source. Omission of the Na gluconate and fructose did notsignificantly change the gel time. The mixed formulation (iron monomer,peroxide primer, and blood) could be held for three hours in amber glassat room temperature with only slight decrease in the gelling time onexposure to light.

Thus, the formulation is sufficiently stable and controllable underoperating room conditions, so that a preparation could be reconstitutedat the start of the operation, and the material would be useful andapplicable to tissue throughout the operation.

EXAMPLE 14

Adherence to tissue at varied concentrations of peroxide and iron.

Areas of excised fresh or frozen-thawed pig lung were primed with aphotoinitiator, and a gel formed on the spot by dripping ofphotoinitiator-containing monomer, using the devices of FIG. 1 or ofFIG. 2. In contrast to the previous example, the iron (ferrousgluconate) was in the primer, and the peroxide in the monomer solution.Gels formed by illumination at peroxide concentrations ranging from 76to 900 ppm, and iron concentrations ranging from 1500 to 5000 ppm, hadat least moderate adherence to tissue after overnight incubations.

EXAMPLE 15

Factorial Screening Experiment for Gel Adherence with respect to varyingquantities of N-vinyl Pyrrolidone, macromonomer concentration andtriethanolamine.

The purpose of this experiment was to examine the effects of varyingamounts acrylic acid, n-vinyl pyrrolidone and triethanolamine in aneffort to understand the interfacial polymerization process variables toget uniform adherent gel coating. The chemistry related variables whichaffect the photopolymerization and gel adherence qualities include Eosinconcentration in tissue, monomer concentration, PEG diacrylate content,and acrylic acid. The factorial experimental design was to screen thestatistical significance of the variables mentioned above, in terms ofindividual and interactive effects. Various combinations of acrylicacid, monomer concentration, triethanolamine and n-vinyl pyrrolidonewere examined in terms of gel-tissue adherence as the response factor.

The experimental results of the factorial experiment outlined below weregraded in accordance to the performance with respect to two tests:

(1) The first time point was the gel adherence at 2 hours, the gradingbeing conducted on a scale of 1-5.

(2) The second time point was the gel adherence in response to low shearforce on adherence at 24 hours, the grading being conducted on a scaleof 1-5.

(3) Grading was conducted by a person who did not know the compositionof the test materials.

Materials

Pig aorta tissue, cut into small sections. The aortic tissue should bepreferably devoid of fatty deposits; CCD camera; dissecting materials;visible light source (514 nm); timer; scintillation counter and vials.

Procedure

(1) As given in the factorial design, there were 16 experiments. 32scintillation vials were marked in sets of duplicate, such as 1.1, 1.2,etc. Since there were 16 experiments, there were 32 vials in total.

(2) A stock solution of 10% acrylic acid was prepared in PBS. 2.50 μl of10% acrylic acid was added to the vials that had 10 ppm of acrylic acidin the experimental design.

(3) Triethanolamine solution was prepared by measuring, by weight, 0.67g triethanolamine: 400 ml of PBS. The solution was pH balanced to 7.4 byadjustment with 6N HCl solution.

(4) The required amounts of VP, triethanolamine, acrylic acid was mixedin 5 ml of PBS.

(5) The required amounts of macromonomer were mixed in, in accordance tothe experiment. pH measurements was taken again, to ensure that thesolutions were at pH 7.4.

(6) The pig aorta tissue was sectioned into small rectangular pieces.All sectioned pieces were chosen, such that the tissue surface wasdevoid of fatty deposits.

(7) 32 scintillation vials were prepared for the storage of the gelledtissue, by the placement of 5 mls of PBS solution in each one.

(8) A 1 mg/ml solution of Eosin in PBS was prepared.

(9) A piece of aortic tissue was placed flat upon a clean surface, and aswab dipped in the eosin solution was pressed upon a spot for exactly 10sec. Another spot was prepared upon the tissue with the eosin dippedswab. The spotted tissue was rinsed in PBS. The tissue section was thengrasped with sharp tweezers and placed in the rectangular 4-well glassslide chambers. The tissue should lie flat inside the chambers.

(10) 400 μl of the macromer solution were placed in the well, and theplate was placed exactly under the collimated beam of the fiber opticcable. The tissue was exposed for exactly 15 sec.

(11) The exposed tissue was grasped gently with tweezers and placed inthe scintillation vial with 5 mls of PBS. The vials were placed insidethe shaker for 2 hours to hydrate.

(12) After 2 hours, the gels were viewed through a microscope to viewthe gel adhering to the tissue. surface. The tissues were graded foradherence, quality and shape on a scale of 1-5. The microscope wasfitted with a SONY CCD Camera. The physical state of the gel can beviewed satisfactorily for grading from 1-5.

(13) After the examination, the vials were placed in the shaker forapproximately 24 hours, to examine the effect of low shear rate on theinterfacial gel.

(14) The gels were examined for gel adherence and quality on a scale of1-5.

                  TABLE 1                                                         ______________________________________                                        Experiments                                                                                         TEA                                                         con. (μl                                                                  Monomer of 60%  Acrylic                                                      Rows Conc. soln) VP (μl) Acid                                            ______________________________________                                        1        10       5          1     0                                            2 10 5 1 10                                                                   3 10 5 3 0                                                                    4 10 5 3 10                                                                   5 10 20 1 0                                                                   6 10 20 1 10                                                                  7 10 20 3 0                                                                   8 10 20 3 10                                                                  9 23 5 1 0                                                                    10 23 5 1 10                                                                  11 23 5 3 0                                                                   12 23 5 3 10                                                                  13 23 20 1 0                                                                  14 23 20 1 10                                                                 15 23 20 3 0                                                                  16 23 20 3 10                                                               ______________________________________                                         (15) The gels were graded according to the following scale:              

                  TABLE 2                                                         ______________________________________                                        Gel Adherence Rating System                                                     GRADE              CRITERION                                                ______________________________________                                        1                Intact                                                         2 Some edges loosened but                                                      otherwise intact                                                             3 50% intact                                                                  4 gel only attached by                                                         some edges, otherwise                                                         not - adhered.                                                               5 Not adhered                                                               ______________________________________                                    

Observations

The adherence score is presented in FIG. 3, in which a higher scorerepresents worse adherence, in contrast to previous examples.

A Factorial Statistical Analyses of the gel adherence scores withrespect to the variables individually, and in interaction with the othervariables (acrylic acid, triethanolamine, N-vinyl pyrrolidone, monomerconcentration) was performed using a Statistical Modeling Package. Pvalues closer to zero indicates the statistical significance (95%confidence interval). The p-values for all the variables and theirinteractive effects were determined.

It was found that the monomer concentration was the dominant influenceand highly significant. The TEA concentration was also significant.Variation in VP and acrylate were not significant in these ranges.

EXAMPLE 16

Further tests of influence of monomer concentration and initiator onadherence of gels to tissues.

Variations in tissue adherence of gels can also be seen in non-primedsystems. As noted in U.S. Pat. No. 5,410,016 to Hubbell et al, , and inDumanian et al, Plastic & Reconst. Surg. 95(5), 901-07 (1995), tissuesealing and adherence may also be obtained without priming.

Adhesion strength was determined by testing the strength of a lap shearof gel, which was formed between a glass and a plastic slide. One slidewas fixed; the other was connected by a string over a pulley, with a cupon the vertical end of the string. After formation of the gel, the cupwas filled from a peristaltic pump, and the stress at which failureoccurred was calculated from the weight of the partially-filled cup atfailure.

As a standard, 150 microliters of a solution containing 23% monomer,type 8KL5, and 300 mg/ml of Irgacure™ initiator, was spread between theslides and polymerized. This produced a high level of adherence, asdetermined by force to failure. A low-adherence control was the samesolution with 10% monomer.

The following variations did not improve adherence: coating each slidewith 10 microliters of 10% monomer solution containing 3× or 10× theamount of initiator, followed by application of 140 microliters of 10%monomer and polymerization. Doubling the precoating to 20 microliterswas also ineffective. However, precoating with 23% monomer, at normalinitiator level, significantly improved overall adherence.

Further testing used bleeding in a cut liver as a test. In thissituation, 23% monomer was much more effective than lot monomer instopping bleeding. It appears from these experiments that higher monomerconcentrations intrinsically adhere to tissue better than lowerconcentrations, at least in the ranges tested.

EXAMPLE 17

Redox interfacial primed system.

It was demonstrated that non-photopolymerization techniques can producegels adherent to tissue. Thinly-sliced ham was soaked in deionizedwater, and a 1 by 2 inch piece was folded in half and the outer edgeswere bonded together. First, 0.1 ml of solution A was applied to thejoint (Solution A contained 10% monomer 8KL5, 0.3% hydrogen peroxide,and 0.3% NVMA (N-vinyl N-methyl acetamide)). Then 0.2 ml of Solution Bwas applied. (Solution B contained 30% 8KL5, 20 mg/ml Ferrous AmmoniumSulfate hexahydrate (Aldrich), 3% fructose, and 0.3% NVMA. Cure wasinstantaneous, and no discoloration of the gel occurred. The bond heldduring overnight soaking in distilled water.

EXAMPLE 18

Sprayed redox system.

Using the above solutions, and with monomer concentrations varying from5% to 10% in solution A and 10% to 30% in solution B, primer (solutionA) was sprayed on semivertical surfaces, followed by solution B.Surfaces were the palm of the experimenter's hand, and petri dishes. Thespraying procedure caused some foaming, but gels were formed on allsurfaces. Because of running of the solutions down the surfaces, gelswere thicker at the bottom but present throughout. In a similarexperiment, the monomer 8KTMC, containing trimethylenecarbonatebiodegradable linkages between the polyethylene glycol and the acrylatecap, seemed to adhere somewhat better than the 8KL5.

EXAMPLE 19

Comparison of peroxygen compounds.

Reductant solutions contained 10% 8KL5 monomer and 8% by volume of aferrous lactate solution, which itself contained 1% ferrous lactate and12% fructose by weight in water. Oxidant solutions contained 10% 8KL5monomer and a constant molar ratio of oxidizer, which was, per ml ofmacromer solution, 10 microliters 30% hydrogen peroxide; 8.8 microliterstert-butyl peroxide; 15.2 microliters cumene peroxide; or 0.02 gpotassium persulfate. 0.5 ml of reductant was mixed with 0.25 mloxidizer, and time to gelation was noted. With hydrogen peroxide,gelling was nearly instantaneous, while with the others there was ashort delay--about 1 second--before gelation. Doubling the t-butylperoxide concentration also produced nearly instantaneous gelling.Hydrogen peroxide produced more bubbles in the gel than the others;persulfate had almost no bubbles. The bubbles in hydrogen peroxide maycome directly from the reactant, as the other compounds have differentdetailed mechanisms of radical formation.

EXAMPLE 20

Effect of reducing sugars.

Using the procedures of example 19, the concentration of ferrous ion wasreduced to 50 ppm, and the fructose was omitted. At 100 ppm HOOH in theoxidizing solution, gel time was increased to 3 to 4 seconds, with bothFe-gluconate and Fe-lactate, but gels were yellow. Addition of 125 ppmascorbic acid to the reducing solution prevented the formation of theyellow color.

EXAMPLE 21

Sodium gluconate addition.

It was found that raising the pH of the iron-peroxide system from 3.7 to5.7 by addition of sodium gluconate had no effect on gelation time.

EXAMPLE 22

Compatibility with ultraviolet photoinitiators.

Solution A contained 1 g 8KL5, 0.4 ml of a ferrous lactate solution(containing 0.4 g ferrous lactate and 4.8 g of fructose in a finalvolume of 40 ml of distilled water), and 8.6 g of distilled water.Solution B contained 1 g of 8KL5, 0.1 ml of 30% hydrogen peroxide, and8.9 g water. Drops of A were allowed to fall into a solution of B,resulting in drops of gel which gradually accumulated at the bottom ofthe solution. If solution B was supplemented with 4% by volume of asolution of 0.2 g of Irgacure™ 651 photoinitiator dissolved (withheating) in 4 ml of Tween™20 detergent, then after making bead dropletsas before, the entire solution could be gelled by application of UVlight. This demonstrates the compatibility of the redox and UV-curingsystems. Moreover, it would be possible to make the redox-cured dropletsfrom a monomer which would degrade either faster or slower than thecontinuous-phase gel, as desired, thereby potentially creating amacroporous gelled composite.

EXAMPLE 23

Relative adherence of gels.

Various gel formulas were compared in their ability to stick to domesticham, versus their ability to adhere the fingers of the hand together. Itwas found that adherence of a formula to one type of surface was onlyweakly predictive, at best, of the adherence to the other. In anotherexperiment, it was found that persulfate-catalysed gels are lessadherent to tissue than comparable t-butyl peroxide gels, but arerelatively more adherent to metal. Thus, the optimal formulation maywell depend on what is to be coated with gel.

EXAMPLE 24

Intra-pleural sealing.

A source of morbidity in lungs is tie formation of bullae, which aresacs formed by separation of the plerua from the lung parenchyma. As amodel for possible repair of bullae, the pleura of a detached lung wasrepeatedly nicked to generate small air leaks. Then a solutioncontaining 15% of 35KL18 macromer, 20 ppm of eosin, 5 milligrams/mlvinylcaprolactam, and 90 mM triethanolamine was injected between thepleura and parenchyma at the sites of the air leaks. The solution spreadpreferentially between the tissue layers, forming a blister-likestructure. The area was transilluminated from the pleural side with isblue-green light for 40 seconds. A flexible gel was obtained, and theair leaks were sealed.

A similar procedure could be applied to other layered tissues to stopleaks and effusion. Because the gel is confined within the tissue,adherence to tissue is not a primary concern. There are a number ofanatomical structures having layered tissue structures suitable for thismethod of sealing a tissue against leakage. Such tissue layers includethe meninges, including the dura, the pia mater and the arachnoid layer;the synovial spaces of the body including the visceral and pareitalpleurae, the peritoneum, the pericardium, the synovia of the tendons andjoints including the bursae, the renal capsule, and other serosae; andthe dermis and epidermis. In each case, a relatively fragile structurecan be sealed by injection of a polymerizable fluid between adjacentlayers, followed by polymerization. Formation of a biodegradable,biocompatible gel layer by non-intrusive processes such asphotopolymerization is especially desirable, because it minimizes traumato the tissue.

EXAMPLE 25

Sealing of an Injured Artery.

In an anesthetized pig, a 1.5 cm lengthwise incision was made in acarotid artery. The incision was closed with interrupted sutures, sothat blood seepage occurred. The injured area was rinsed with saline,and the blood was suctioned from the treatment zone. The treatment zonewas primed with 1 mg/ml eosin in buffer (TEOA in 1/3 normal phosphatebuffered saline). A macromer solution was applied with a smallpaintbrush to the treatment zone under illumination with blue-greenargon ion laser light. In a first artery, the macromer solutioncontained 15% 35KC3.3, 4 mg/ml N-vinylcaprolactam, and 20 ppm eosin. Ina second artery, the macromer was type 35KL18, and the macromer solutionhas a paste-like consistency. Four applications (0.5 to 1.0 ml each)were required to seal all leaks. It was easier to build thickness withthe paste-like monomer. The pig was held under anesthesia for an hour,and the injury sites were reexamined and found to be still sealed.

EXAMPLE 26

Adherence of coating layers to living tissue surfaces.

An experiment was performed to evaluate the acute adherence of aformulation of 20% macromer 35KT8A2. with redox/eosin primer touninjured tissue in situ. An immature pig (est. 35 kg) was maintained inan anesthetized condition and various tissues and prosthetic implants(described below) were surgically exposed or prepared. Care was taken toprevent injury to the tissues; however, the dissection of connectivetissue often resulted in a roughened surface where the primer/polymerwas applied.

The primer and macromer were applied with separate paint brushes, andlight was delivered from a bare 2 mm diameter optical fiber. The lightsource was periodically checked and consistently emitted approx. 580 mWof visible light through the course of the experiment at the distal tipof the delivery fiber.

The acute adherence was graded on a 1-4 scale, where 3 or better isconsidered acceptable: "4": cohesive failure into small pieces when thedeposited gel is gripped with blunt tweezers and pulled perpendicularand/or parallel to the tissue surface.

"3": cohesive failure with larger fragments.

"2": combined cohesive/adhesive failure.

"1": adhesive failure, gel lifts off in continuous film.

A. Adherence to tissues (Tissue/adherence grade):

1) Lower stomach (proximal to pylorus)--3.5 The stomach was reexaminedafter 1 hour indwelling--<3.5. Still adherent, but less than at time=0.Tear strength deteriorated.

2) Common bile duct--3.5.

3) Urinary bladder--3.8 (Punctate bleeding was noted on the bladder; itwas confirmed that the causes were brushes and manipulation).

4) Ureter--3.5-3.8;

5) Large bowel (descending colon 8 cm anterior to pubic bone)--4.0

6) Esophagus--3.5.

7) Patellar tendon (2 cm proximal to tibial attachment)--3.5

8) Cartilage (trochlea groove of knee)--2.5 This tissue didn't stainwith eosin; polymerized gel peeled off in sheets. Removal of upperhyaline layer, deep enough for minor blood oozing to appear, improvedscore to 2.8.

B. Adherence to other implantable materials.:

9) Collagen coated Dacron patch--3 This was a Datascope woven Dacrongraft material 8 mm diameter. Collagen impregnated; 6-0 Prolene sutures.

10) Abdominal aortic graft--3.5. This was a Meadox Dacron double velour(inside/outside); 6 mm Inside diameter; Cat No. 174406. Lot No245246.Sterilized 1986. The graft was preclotted in autologous blood.The animal was heparinized before implantation.

11) Gore FEP (fluorinated ethylene propylene) in vitro test--0. Materialwould not stain; cured polymer slid off without effort.

12) Carotid Gore patch--2.5-3. Polymer adhered to sutures andsurrounding tissue.

13) Hernia mesh--2.5 (more or less). Polymer was. used to anchor themesh (by U.S. Surgical) onto external abdominal oblique fascia. Thepolymer was suitable for positioning, but did not provide "structural"anchoring.

EXAMPLE 27

Process for sealing medical devices to body tissues

There is a need to seal or bond medical device surfaces to tissue. To besuccessful, this application requires the sealant or adhesive to formstrong bonds to both the device and the tissue. Important examples ofthis application apply to sustained use devices such as percutaneouscatheters (e.g. central venous catheters), percutaneous cannulae (e.g.for ventricular assist devices), urinary catheters, percutaneouselectrical wires, ostomy appliances, electrodes (surface and implanted)and the like. In such devices, there is a tendency of the implant ordevice to move relative to the surrounding tissue. Such movement canallow entry of microorganisms, or can intensify the reaction of thetissue to the implant. Moreover, when a device is insertedpercutaneously, then during the process of healing the epidermis incontact with the implant may undergo "marsupialization", or theformation of a partial pouch along the surface of the implant. This canretard healing of the percutaneous opening, following removal of thedevice.

In scope, the process includes sealing the device/tissue interface forany medical device that crosses or disrupts a tissue layer whosecontinuity provides a natural defense mechanism against infection orbodily fluid loss (skin, mucous membranes). This technology is alsoapplicable to obliterating potential space between implanted devicesthat do not allow tissue ingrowth/ongrowth and the implant bed, servingto reduce device movement which is a cause of chronic inflammation.These tissue-device sealants may also serve as matrices for drugdelivery, for example the delivery of antimicrobials to preventinfection.

Bioabsorbable hydrogels and non-absorbable analogs are appealing forthese applications in that they may be formed in place to seal (or"caulk") around the device. Hydrogels usually adhere poorly tohydrophobic device surfaces which comprise most of the examples listedabove.

However, a process is provided herein which produces a strong attachmentof hydrogel to a hydrophobic surface during in situ polymerization ofhydrogel components. It involves applying a primer containing adequateconcentrations of an initiator of polymerization (Eosin Y and/or otheringredients) to a hydrophobic surface (in the example below,polystyrene, in a 12 well plate) following with a sealant compositionbased on a polymerizable macromer (in this example containingtriethanolamine co-initiator), and effecting polymerization. Thedifferent embodiments, 27.1-27.3, are described below.

27.1: Into one well of a 12 well microtiter dish was placed 0.1 ml of aprimer solution containing 500 ppm eosin with ferrous gluconate (5mg/ml), fructose(10 mg/ml), and macromer 3.3KL5A2 (30%). Then 0.9 ml wasadded of a solution containing 12.8% of macromer F127T4A2 (i.e.,poloxamer Pluronic F127, with 4 units of trimethylene carbonate andacrylate end caps), 125 ppm t-butyl peroxide, 90 mM triethanolamine and0.4% VC (N-vinylcaprolactam). The mixture partially gelled on mixing,but the gel was not coherent. After illumination with blue light for2×20 sec., a coherent gel was formed. However it was not tightly adheredto the surface of the plastic.

27.2: The experiment was repeated, but the eosin concentration wasraised to 2000 ppm. Initially the solution did not gel as well, but onillumination the gel adhered strongly to the plastic.

27.3: The experiment was repeated at 2000 ppm eosin concentrations, butwithout the "redox" components (ferrous gluconate, fructose, t-butylperoxide). Adherence was stronger at 2000 ppm eosin (alone) than at 500ppm even with redox materials, although not as strong as with the redoxcomponents present.

The results are compatible with the idea that the eosin was absorbing tothe surface of the plastic during the course of the experiment. Tovalidate this, a solution containing 12.8% macromer (F127T4A2), theusual VC and buffer, no redox components, and 2000 ppm eosin was appliedto a well and allowed to stand for about 10 seconds. The gel wasstrongly adherent. In a comparable experiment at 100 ppm eosin, the gelwas formed but adhered weakly.

Thus, a critical variable here appears to be the level ofphotoinitiator--here eosin--in the primer. Relatively highconcentrations (2000 ppm) gave stronger bonds of hydrogel to polystyrenethan lower amounts. The use of "redox" coinitiators gave stronger gels,but high Eosin levels gave strong bonds with or without "redox"coninitiation.

In other experiments, it was demonstrated that the system that gave thestrongest bonds to the polystyrene also gave very strong bonds to animaltissue (cadaveric goat gingiva). The strong bonding of sealant topolystyrene 12 well plates may thus used (in the absence of tissue)todemonstrate the tissue bonding capability of a particular hydrogel, thusminimizing experimentation. This system, applied simultaneously to atissue and a hydrophobic device (via application of primer, sealant, andlight) would thus appear to result in an effective tissue-to-devicesealant with wide-ranging applicability.

EXAMPLE 28

Use of redox-assisted photoinitiation in treatment of injured arteries.

The interior of a rabbit carotid artery was injured by scraping with aninflated balloon catheter. The injured area was then isolated with a twoballoon catheter, and the injured zone was flushed with saline;stainedon its surface with an initiator solution, containing 20 ppm eosin Y inPBS (phosphate-buffered saline, pH 7.4);further flushed with saline toremove unbound eosin;treated with a buffered solution containing 90 mMTEOA (triethanolamine), pH 7.4; 30% by weight of polymerizable macromer;0.2% to 0.25% of vinylpyrrolidone or vinylcaprolactam; and optionally 50ppm of ferrous sulfate. The treatment zone was then exposed to 100mW/sq. cm.of green light from an argon laser for 20 seconds. Theballoons were collapsed and blood flow was permitted to resume,resulting in flushing of excess macromer from the zone into the rest ofthe circulation. In various tests, it was found that a thin layer of gelwas formed on the inside of the artery both with and without theaddition of ferrous ion. It was further found that the layer persistedfor longer times in the presence of the ferrous ion.

To better understand this system, gels were formed in test cells, andtheir mechanical properties after various lengths of illumination werecompared. It was found that the addition of iron resulted in gels whichwere better cured and which were relatively less sensitive to the exactconcentration of other reagents, or to the duration of illumination.This is shown in more detail in Table 3:

                  TABLE 3                                                         ______________________________________                                        Ratio of Modulus at 20 sec. to 90 sec. of                                       illuminatian                                                                                              20   100                                           Redox ppm ppm                                                                Illumination conc. eosin eosin                                              ______________________________________                                        100 mW/cm2  50 ppm Fe     93%    83%                                              0 ppm Fe 63% 14%                                                            400 mW/cm2 50 ppm Fe 98% 77%                                                ______________________________________                                         Conditions: 30% 3.3KL5 in 90 mM TEOA pH 7.4 and 2 μL VP/mL            

The ratio of the gel modulus at 20 sec. illumination to 90 seconds is ameasure of the rapidity of complete polymerization of the gel. Highernumbers denote faster polymerization. It can be seen that the additionof iron markedly accelerates the cure, and that this effect is morepronounced at 100 ppn eosin, where the underlying variation is greater,and likewise at lower light levels.

EXAMPLE 29

Redox systems with Urethanes, Acids and Amides, using Ceric Ion.

The objective of the experiment was to determine the feasibility ofmaking polar-ionic macromers using a Ce-IV based redox system withurethanes, carboxylates or amides as reductant. A special macromer wasmade (3.3KL5A1: 3.3K PEG; 5 lactides; 1 acrylate) and end-capped withdiisocyanate to form a urethane by standard procedures.

The different embodiments, 29.1-29.4, are described below.

29.1: Add 1 ml of methacrylic acid to 10 ml of 2.25 wt. % Ceric ammoniumnitrate in water ("Ce solution"; has yellow color). A white precipitatewas formed immediately; the yellow color faded over time.

29.2: Add 10 ml Ce solution to a 10 ml solution containing 0.5 ml aceticacid and 0.5 ml methyl acrylate. A white precipitate formed immediately,and the yellow color gradually faded.

29.3: Add 1 g of the NCO-end capped initiator to 10 ml of Ce solution,and mix with 10 ml of a 50% w/v solution of AMPS (acrylamido methylpropanesulfonic acid). The solution remained yellow and unprecipitated.However, after standing overnight at room temperature the solution hadbecome colorless and highly viscous, and was not filterable through a0.2 micron filter. This suggests a high degree of polymerization,perhaps with some crosslinking.

29.4: A carboxylate-terminated macromer was made by treating 3.3KL5A1.0with succinic anhydride. The purified reprecipitated polymer wasdissolved in deionized water (0.39 g /7 ml) and 2.0 g of AMPS was added.The pH was adjusted to 3.8 with NaOH. Then 55 mg. of Ce(IV) ammoniumnitrate was added (approximately stoichiometric with the expected numberof carboxyl groups). The volume was adjusted to 10 ml. with water. Thesolution rapidly became turbid and increased in viscosity, and appearedto be crosslinked to a gel within about 1 hr. The resulting gel could bedissolved by pH 13 NaOH solution in about 1 hr., showing that thecrosslinks involved the degradable ester moieties.

It appeared that both carboxylic groups and urethane groups can serve asreductants for ceric ion in a redox-catalysed polymerization of anunsaturated group. Other groups known to be effective in such reactionscan also be used where the conditions are physiologically reasonable.

EXAMPLE 30

Adherence of medical device material to tissue.

In this example, direct adhesion of a typical medical polymer to tissueis demonstrated. It is further shown that the location of the plane offracture of the composite can be controlled by selection ofconcentration and type of photoinitiator.

Microscope-slide-sized pieces of Pellethane (Dow) extruded polyurethanesheet were washed with acetone to remove impurities and dried in avacuum oven. They were then stained with a solution of 2000 ppm Eosin Yin PBS, as above, for several minutes until pink staining of thepolyurethane was observed. Sheets were rinsed in water and air dried.

Pieces of abdominal wall were excised from a euthanized rat, and usedwith the peritoneal side "up" ("tissue"). Tissue was clamped to a glassslide with binder clips. Thin Teflon spacers were placed on top of thetissue. Dried sheets of urethane were clamped into the sandwich,eosin-stained side towards the tissue, forming a thin chamber betweenthe polyurethane and the tissue, typical of clearances found in medicalpractice. Four combinations of solutions were tested.

The different embodiments, 30.1-30.4 are described below.

30.1: About 0.2 ml of a primer solution containing 2000 ppm eosin in PBSwas infused into the chamber, and was removed by wicking after about aminute. A macromer solution (about 0.2 ml) was added, containing 12.8%F127T4A2 macromer (as in example 27), 90 mM TEOA and 0.4% VC (vinylcaprolactone), and, in this experiment, 2000 ppm eosin. The chamber wastransilluminated through the glass slide and rat flap for 40 seconds.The macromer did not completely polymerize, and on removal of the clampsthe tissue separated from the urethane without appreciable force.

30.2: The above experiment was repeated, but the eosin concentration inthe macromer solution was reduced to 20 ppm. Polymerization wascomplete. On separation of the tissue from the urethane, the gelfractured while remaining adherent to both tissue and to the urethane.

30.3: The above experiment 30.2 was repeated, except that the redoxaccelerator t-butyl peroxide was present in the macromer solution at 125ppm, and the primer contained Ferrous gluconate and fructose as inExample 27.1. The gel was completely polymerized. On attempting to peelthe tissue from the urethane, the tissue tore--i.e., both the gel andits bonds, to both tissue and device, were stronger than the tissueitself.

30.4: Experiment 30.2 was repeated, except that the concentration ofeosin in the primer was reduced to 20 ppm. Polymerization was complete.On peeling the tissue, failure of adhesion occurred at the interfacebetween the gel and the tissue.

This example demonstrates that by selection of initiator types andconcentrations, the fracture plane of a device bonded to a tissue by agel can be varied at will, and behaves in a reasonable and predictableway. Although the gel compositions in this example were degradable, thepeeling was done at short times, and the results will extrapolatedirectly to non-degradable gels.

Modifications and variations of the present invention will be obvious tothose skilled in the art. Such modifications and variations are intendedto come within the scope of the appended claims.

We claim:
 1. A process for reducing leakage of bodily fluidscomprising:applying a polymerization initiator to an area of a tissuesurface, applying a solution containing a biodegradable, biocompatible,polymerizable monomer to the initiator-coated surface in aninitiator-incorporating manner; and polymerizing the monomer to seal thearea and to reduce leakage of the bodily fluids through the area.
 2. Theprocess of claim 1 in which the bodily fluid is selected from the groupconsisting of blood, serum, air, urine, bowel contents, cerebrospinalfluid, tears, and mucus.
 3. The process of claim 2 in which the fluid isair.
 4. The process of claim 2 wherein the body area is part of therespiratory tract.
 5. The process of claim 4 wherein the body area is alung.
 6. The process of claim 1 wherein the polymer isphotopolymerizable and the initiator is a photoinitiator.
 7. The processof claim 6 wherein the photoinitiator is an eosin.
 8. The process ofclaim 1 in which the area to be treated is coated with a photoinitiator,and the polymerizable monomer is applied in a solution containing aphotoinitiator.
 9. The process of claim 1 in which the tissue surface isthe surface between two tissue layers which are adhered together whenthe material is polymerized.
 10. The process of claim 9 where the tissuelayers are selected from the meninges, the synovial spaces of the body,the peritoneum, the pericardium, the synovia of the tendons and joints,the serosae, and the dermis and epidermis.
 11. The process of claim 4 inwhich the solution further comprises biologically active materials forrelease to the tissue.
 12. The process of claim 11 in which thebiologically active substance is selected from the group consisting ofproteins, peptides, organic synthetic molecules, inorganic compounds,natural extracts, nucleic acids, lipids, steroids, carbohydrates, andcombinations thereof.
 13. The process of claim 9 in which the body areais selected from the site of an anastomosis, a suture, a staple, apuncture, an incision, a laceration, and an apposition of tissue. 14.The process of claim 1 further comprising applying additional polymerlayers onto the first polymer coating layer, wherein the concentrationof the polymerizable material in the solution used to prepare the firstlayer is higher than the concentration of polymerizable material in thesolutions used to prepare the additional layers.